CN1390204A - Fungicidal heterocyclic aromatic amides and their compositions, methods of use and preparation - Google Patents
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Abstract
根据式(I)的杂环芳族酰胺(HAA),其中X1－X4、M、Z和A是如本文所定义的。本发明还涵盖它们的水合物、盐和配合物。这些化合物可用作杀真菌剂。
Heterocyclic aromatic amides (HAAs) according to formula (I), wherein X1 – X4 , M, Z, and A are as defined herein. This invention also covers their hydrates, salts, and complexes. These compounds can be used as fungicides.
Description
优先权Priority
本申请所要求的优先权基础是分别于1999年8月20日和1999年8月23日向美国专利与商标局提交的临时申请60/149,977和60/150,248，其全部内容引用在此作为参考文献。临时申请60/149,977和60/150,248都要求于1999年7月20日提交的临时申请60/144,646的优先权，其全部内容引用在此作为参考文献。The basis of priority for which this application is claimed is Provisional Applications 60/149,977 and 60/150,248, filed August 20, 1999 and August 23, 1999, respectively, in the United States Patent and Trademark Office, the entire contents of which are incorporated herein by reference . Provisional applications 60/149,977 and 60/150,248 both claim priority to provisional application 60/144,646, filed July 20, 1999, which is hereby incorporated by reference in its entirety.
本申请要求于2000年7月20日提交的非临时申请09/620,662作为优先权，其全部内容引用在此作为参考文献。This application claims priority from non-provisional application 09/620,662, filed July 20, 2000, the entire contents of which are hereby incorporated by reference.
发明背景Background of the Invention
发明领域field of invention
本发明涉及杀真菌组合物和方法的领域。更确切地说，本发明涉及新颖的杀真菌的杂环芳族酰胺和向植物病原体所在地施用杀真菌有效量该化合物的方法。本发明还涉及可用于制备杂环芳族酰胺和它们的杀真菌组合物的方法。The present invention is in the field of fungicidal compositions and methods. More specifically, the present invention relates to novel fungicidal heterocyclic aromatic amides and methods of applying fungicidally effective amounts of the compounds to the locus of plant pathogens. The invention also relates to processes useful for the preparation of heterocyclic aromatic amides and their fungicidal compositions.
现有技术的说明Description of prior art
本领域熟知有各种抗真菌的组合物和方法。例如，抗霉素已被鉴定是由链霉菌属产生的一种天然存在的物质，具有抗生性质(Barrow，C.J.等《抗生素杂志》1997，50(9)，729)。还已发现这些物质是有效的杀真菌剂(《Merck索引》第12版，S.Budavari，Ed.，Merck andCo.，Whitehouse Station，N.J.，1996，p.120)。WO 97/08135描述了酰基氨基水杨酸酰胺是有用的杀虫剂。EP-A-O-661269公开了取代的杂环羧酸酰胺是有用的医疗药物。JP-A-7-233165公开了具有3-羟基吡啶羧基的抗真菌二内酯，具有抗霉菌作用。后者这些化合物的异丁酰基、甲基巴豆酰基、异戊酰基和2-甲基丁酰基衍生物进一步被描述在下列参考文献中：《四面体》1998，54，12745-12774；《抗生素杂志》1997，50(7)，551；《抗生素杂志》1996，49(7)，639；《抗生素杂志》1996，49(12)，1226；和《四面体快报》1998，39，4363-4366。Various antifungal compositions and methods are well known in the art. For example, antimycin has been identified as a naturally occurring substance produced by Streptomyces sp. with antibiotic properties (Barrow, C.J. et al. J. Antibiotics 1997, 50(9), 729). These substances have also been found to be effective fungicides ("Merck Index" 12th Ed., S. Budavari, Ed., Merck and Co., Whitehouse Station, N.J., 1996, p. 120). WO 97/08135 describes acylaminosalicylic acid amides as useful insecticides. EP-A-O-661269 discloses that substituted heterocyclic carboxylic acid amides are useful medical agents. JP-A-7-233165 discloses an antifungal dilactone having a 3-hydroxypyridine carboxyl group, which has an antifungal effect. The isobutyryl, methylcrotonyl, isovaleryl and 2-methylbutyryl derivatives of these latter compounds are further described in the following references: Tetrahedron 1998, 54, 12745-12774; Journal of Antibiotics 1997, 50(7), 551; Journal of Antibiotics 1996, 49(7), 639; Journal of Antibiotics 1996, 49(12), 1226; and Tetrahedron Letters 1998, 39, 4363-4366.
不过，对新颖的杀真菌剂仍然存在需求。本发明提供这样的杀真菌剂，它们的残效高，在更低施用率下活性更高，具有治疗活性，并且功效谱更宽。However, there remains a need for novel fungicides. The present invention provides fungicides with high residual efficacy, higher activity at lower application rates, therapeutic activity, and a broader spectrum of efficacy.
发明概述Invention Summary
简要描述本发明的一个方面的话，提供了包含杂环芳族酰胺(HAA)的式I化合物：
本发明还提供杀真菌组合物，包含HAA与植物学上可接受的载体和/或稀释剂的组合。还公开了杂环芳族酰胺化合物和组合物的使用方法。The present invention also provides fungicidal compositions comprising HAA in combination with a phytologically acceptable carrier and/or diluent. Methods of using the heterocyclic aromatic amide compounds and compositions are also disclosed.
本发明的目的是提供HAA及其组合物，它们是有效的抗真菌剂。It is an object of the present invention to provide HAAs and compositions thereof which are effective antifungal agents.
本发明的另一个目的是提供用于控制和/或预防真菌感染的方法，该方法包括施用HAA和含有它们的组合物。Another object of the present invention is to provide methods for the control and/or prevention of fungal infections comprising the administration of HAAs and compositions containing them.
本发明的进一步目的和优点通过下列说明将是显而易见的。Further objects and advantages of the present invention will become apparent from the following description.
发明的一般范围General scope of invention
本发明涉及各种HAA化合物，它们是有效的抗真菌剂。还包括HAA化合物的制剂和使用HAA化合物和制剂的方法。本发明还涵盖HAA化合物的制备方法和它们作为杀真菌剂的用途。The present invention relates to various HAA compounds which are effective antifungal agents. Also included are formulations of HAA compounds and methods of using the HAA compounds and formulations. The invention also encompasses processes for the preparation of HAA compounds and their use as fungicides.
HAA化合物
本发明的新颖的抗真菌HAA化合物是由下式I所描述的：式I其中：a)
(i)每个X1-X4独立地是O、S、NR’、N、CR”或一条键；(i) each X 1 -X 4 is independently O, S, NR', N, CR" or a bond;
(ii)X1-X4至多有一个是O、S或NR’；(ii) at most one of X 1 -X 4 is O, S or NR';
(iii)X1-X4至多有一个是一条键；(iii) At most one of X 1 -X 4 is a bond;
(iv)若任意X1-X4之一是S、O或NR’，则相邻的X1-X4之一必须(iv) If any one of X 1 -X 4 is S, O or NR', then one of the adjacent X 1 -X 4 must
代表一条键；和represents a key; and
(v)X1-X4至少有一个必须是O、S、NR’或N；其中(v) At least one of X 1 -X 4 must be O, S, NR' or N; where
R’是H、C1-C3烷基、C2-C3烯基、C2-C3炔基、羟基、酰氧基、R' is H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, hydroxyl, acyloxy,
C1-C6烷氧基甲基、CHF2、环丙基或C1-C4烷氧基；R”独立地是H、C 1 -C 6 alkoxymethyl, CHF 2 , cyclopropyl or C 1 -C 4 alkoxy; R" is independently H,
卤素、氰基、羟基、C1-C3烷基、C1-C3卤代烷基、环丙基、C1-C3 Halogen, cyano, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyclopropyl, C 1 -C 3
烷氧基、C1-C3卤代烷氧基、C1-C3烷硫基、芳基、C1-C3 NHC(O)Alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, aryl, C 1 -C 3 NHC(O)
烷基、NHC(O)H、C1-C3卤代烷硫基、C2-C4烯基、C2-C4卤代烯基、Alkyl, NHC(O)H, C 1 -C 3 haloalkylthio, C 2 -C 4 alkenyl, C 2 -C 4 haloalkenyl,
C2-C4炔基、C2-C4卤代炔基或硝基，其中相邻的R”取代基可以C 2 -C 4 alkynyl, C 2 -C 4 haloalkynyl or nitro, wherein the adjacent R" substituents can be
构成一个环或者相邻的R’与R”取代基可以构成一个环；Form a ring or adjacent R' and R" substituents can form a ring;
b)Z是O、S或NORz，其中RZ是H或C1-C3烷基；和b) Z is O, S or NOR z , wherein R Z is H or C 1 -C 3 alkyl; and
c)A代表c) A stands for
(i)C1-C14烷基、C2-C14烯基或C2-C14炔基，所有它们都可以是支链或直链的、未取代的或者被卤素、羟基、硝基、芳酰基、芳氧基、C1-C8酰氧基、C1-C6烷硫基、芳硫基、芳基、杂芳基、杂芳硫基、杂芳氧基、C1-C6酰基、C1-C6卤代烷基、C1-C6烷氧基或C1-C6卤代烷氧基取代，(i) C 1 -C 14 alkyl, C 2 -C 14 alkenyl or C 2 -C 14 alkynyl, all of which may be branched or straight chained, unsubstituted or replaced by halogen, hydroxy, nitro , aroyl, aryloxy, C 1 -C 8 acyloxy, C 1 -C 6 alkylthio, arylthio, aryl, heteroaryl, heteroarylthio, heteroaryloxy, C 1 - C 6 acyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy substituted,
(ii)C3-C14环烷基，含有0-3个杂原子和0-2个不饱和度，可以是未取代的或者被卤素、羟基、C1-C6烷基、C1-C6卤代烷基、氰基、硝基、芳酰基、芳氧基、杂芳氧基、C1-C6烷硫基、芳硫基、杂芳硫基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C8酰氧基、芳基、杂芳基、C1-C6酰基、芳氧羰基、杂芳氧羰基、C1-C6烷氧羰基或酰氨基取代，该酰氨基是未取代的或者被一个或两个C1-C6烷基取代，(ii) C 3 -C 14 cycloalkyl, containing 0-3 heteroatoms and 0-2 degrees of unsaturation, which may be unsubstituted or replaced by halogen, hydroxyl, C 1 -C 6 alkyl, C 1 - C 6 haloalkyl, cyano, nitro, aroyl, aryloxy, heteroaryloxy, C 1 -C 6 alkylthio, arylthio, heteroarylthio, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 8 acyloxy, aryl, heteroaryl, C 1 -C 6 acyl, aryloxycarbonyl, heteroaryloxycarbonyl, C 1 -C 6 alkoxycarbonyl or Substituted by amido group, the amido group is unsubstituted or substituted by one or two C 1 -C 6 alkyl groups,
(iii)C6-C14二或三环系统，含有0-3个杂原子和0-2个不饱和度，可以是未取代的或者被卤素、羟基、C1-C6烷基、C1-C6卤代烷基、氰基、硝基、芳酰基、芳氧基、杂芳氧基、C1-C6烷硫基、芳硫基、杂芳硫基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C8酰氧基、芳基、杂芳基、C1-C6酰基、芳氧羰基、杂芳氧羰基、C1-C6烷氧羰基或酰氨基取代，该酰氨基是未取代的或者被一个或两个C1-C6烷基取代，(iii) C 6 -C 14 bi- or tricyclic ring systems containing 0-3 heteroatoms and 0-2 degrees of unsaturation, which may be unsubstituted or replaced by halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, nitro, aroyl, aryloxy, heteroaryloxy, C 1 -C 6 alkylthio, arylthio, heteroarylthio, C 1 -C 6 alkoxy radical, C 1 -C 6 haloalkoxy, C 1 -C 8 acyloxy, aryl, heteroaryl, C 1 -C 6 acyl, aryloxycarbonyl, heteroaryloxycarbonyl, C 1 -C 6 alkoxy Carbonyl or amido substitution, the amido is unsubstituted or substituted by one or two C 1 -C 6 alkyl groups,
(iv)芳基或杂芳基，它可以是未取代的或者被硝基、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、芳基、杂芳基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、芳氧羰基、杂芳氧羰基、C1-C6烷氧羰基或酰氨基取代，该酰氨基是未取代的或者被一个或两个C1-C6烷基、C1-C6烷硫基、C1-C6烷基磺酰基、C1-C6烷基亚磺酰基、C1-C6 OC(O)烷基、OC(O)芳基、C3-C6 OC(O)环烷基、C1-C6 NHC(O)烷基、C3-C6 NHC(O)环烷基、NHC(O)芳基、NHC(O)杂芳基、C3-C6环烷硫基、C3-C6环烷基磺酰基、C3-C6环烷基亚磺酰基、芳氧基、杂芳氧基、杂芳硫基、杂芳基亚磺酰基、杂芳基磺酰基、芳硫基、芳基亚磺酰基、芳基磺酰基、C(O)RY、C(NORX)RY取代，其中任何含有烷基或环烷基的取代基都可以被一个或多个卤素取代，其中任何含有芳基或杂芳基的取代基也都可以是未取代的或者被卤素、氰基、硝基、芳酰基、芳氧基、芳基、杂芳基、C1-C6酰基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷氧羰基或酰氨基取代，该酰氨基是未取代的或者被一个或两个C1-C6烷基取代，其中RY和RX独立地是H、C1-C6烷基、C2-C6烯基、C3-C6环烷基、芳基或杂芳基，和(v)
Q1、Q2是O或S；Q 1 and Q 2 are O or S;
W是O、CH2、CHR6或一条键；W is O, CH 2 , CHR 6 or a bond;
R1是C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、芳基或杂芳基；R 1 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, aryl or heteroaryl;
R2是H、C1-C3烷基、C2-C5烯基或C2-C5炔基；R 2 is H, C 1 -C 3 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl;
R3是H、R1、OR1、OC(O)R1、OC(O)OR1或OC(O)NR1R6；R 3 is H, R 1 , OR 1 , OC(O)R 1 , OC(O)OR 1 or OC(O)NR 1 R 6 ;
R4和R5独立地是H、C1-C6烷基或C2-C6烯基，其条件是R4加R5的碳数之和是六或以下，进一步的条件是R4和R5可以连接成为一个C3-C6环；R 4 and R 5 are independently H, C 1 -C 6 alkyl or C 2 -C 6 alkenyl, provided that the sum of the carbon numbers of R 4 plus R 5 is six or less, further provided that R 4 and R 5 can be connected to form a C 3 -C 6 ring;
R6和R7独立地是H、C1-C6烷基、C3-C6环烷基、C2-C5烯基或C2-C5炔基，其条件是R6和R7至少有一个是H；其条件是若
其中R”是H或OCH3，则where R" is H or OCH 3 , then
R1不是异丁酰基、甲基巴豆酰基、异戊酰基或2-甲基丁酰基；d)M代表H、Si(t-Bu)Me2、Si(Ph)Me2、SiEt3、SiMe3、C(Z)R8、SO2R9，其中R8是H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、烷氧基烷基、卤代烷基、烷氧基烯基、卤代烯基、烷氧基炔基、卤代炔基、取代与未取代的芳基烷基、取代与未取代的芳基烯基、取代与未取代的芳基炔基、取代与未取代的芳基、取代与未取代的杂芳基、C1-C6烷氧基、C3-C6环烷氧基、C1-C6卤代烷氧基、C2-C6烯氧基、C2-C6卤代烯氧基、C2-C6炔氧基、C2-C6卤代炔氧基、C1-C6硫代烷氧基、取代与未取代的芳基烷氧基、取代与未取代的芳基烯氧基、取代与未取代的芳基炔氧基、取代与未取代的芳氧基、取代与未取代的杂芳氧基、氨基，该氨基是未取代的或者被一个或两个C1-C6烷基取代，R9是C1-C6烷基、C2-C6烯基、C3-C6炔基、C3-C6环烷基、芳基或杂芳基。R 1 is not isobutyryl, methylcrotonyl, isovaleryl or 2-methylbutyryl; d) M represents H, Si(t-Bu)Me 2 , Si(Ph)Me 2 , SiEt 3 , SiMe 3 , C(Z)R 8 , SO 2 R 9 , wherein R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkane radical, alkoxyalkyl, haloalkyl, alkoxyalkenyl, haloalkenyl, alkoxyalkynyl, haloalkynyl, substituted and unsubstituted arylalkyl, substituted and unsubstituted aryl Alkenyl, substituted and unsubstituted arylalkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 haloalkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 haloalkynyloxy, C 1 -C 6 thioalkoxy, substituted and unsubstituted arylalkoxy, substituted and unsubstituted arylalkenyloxy, substituted and unsubstituted arylalkynyloxy, substituted and unsubstituted aryloxy , substituted and unsubstituted heteroaryloxy, amino, the amino is unsubstituted or substituted by one or two C 1 -C 6 alkyl groups, R 9 is C 1 -C 6 alkyl, C 2 -C 6 Alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, aryl or heteroaryl.
本文所用的术语烷基、烯基、炔基等在它们的范围内包括直链和支链基团；术语烯基、亚烯基等打算包括含有一条或多条双键的基团；术语炔基、亚炔基等打算包括含有一条或多条叁键的基团。本文所用的环烷基指的是含有0-3个杂原子和0-2个不饱和度的C3-C14环烷基。二或三环系统指的是含有0-3个杂原子和0-2个不饱和度的C6-C14脂族环系。上述术语进一步涵盖取代或未取代的形式。除非另有具体限定，取代的形式指的是被一个或多个基团取代，取代基选自卤素、羟基、氰基、硝基、芳酰基、芳氧基、芳基、芳硫基、杂芳基、杂芳氧基、杂芳硫基、C1-C8酰基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷硫基、C1-C6卤代烷硫基、芳氧羰基、杂芳氧羰基、C1-C6烷氧羰基或酰氨基，该酰氨基是未取代的或者被一个或两个C1-C6烷基取代。所有上述术语和定义假设符合化学键与应变能的规则。As used herein, the terms alkyl, alkenyl, alkynyl, etc. include within their scope straight and branched chain groups; the terms alkenyl, alkenylene, etc. are intended to include groups containing one or more double bonds; the term alkyne Groups, alkynylene groups, etc. are intended to include groups containing one or more triple bonds. Cycloalkyl as used herein refers to a C3 - C14 cycloalkyl group containing 0-3 heteroatoms and 0-2 degrees of unsaturation. A bi- or tricyclic ring system refers to a C 6 -C 14 aliphatic ring system containing 0-3 heteroatoms and 0-2 degrees of unsaturation. The above terms further encompass substituted or unsubstituted forms. Unless otherwise specifically defined, the substituted form refers to being substituted by one or more groups, and the substituents are selected from halogen, hydroxyl, cyano, nitro, aroyl, aryloxy, aryl, arylthio, hetero Aryl, heteroaryloxy, heteroarylthio, C 1 -C 8 acyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, aryloxycarbonyl, heteroaryloxycarbonyl, C 1 -C 6 alkoxycarbonyl or amido, the amido is unsubstituted or replaced by one or two C 1 -C 6 alkyl substitution. All of the above terms and definitions assume compliance with the rules for chemical bonds and strain energies.
本文所用的术语芳基指的是取代的苯基或萘基。术语杂芳基指的是任何含有一个或多个杂原子的5或6元芳族环；这些杂芳族环还可以与其他芳族系统稠合。上述术语进一步涵盖取代或未取代的形式。取代的形式指的是被一个或多个基团取代，取代基选自硝基、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、芳基、杂芳基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷硫基、C1-C6烷基磺酰基、C1-C6烷基亚磺酰基、C1-C6 OC(O)烷基、OC(O)芳基、C3-C6 OC(O)环烷基、C1-C6 NHC(O)烷基、C3-C6 NHC(O)环烷基、NHC(O)芳基、NHC(O)杂芳基、C3-C6环烷硫基、C3-C6环烷基磺酰基、C3-C6环烷基亚磺酰基、芳氧基、杂芳氧基、杂芳硫基、杂芳基亚磺酰基、杂芳基磺酰基、芳硫基、芳基亚磺酰基、芳基磺酰基、C(O)RY、C(NORX)RY，其中RY和RX独立地是H、C1-C6烷基、C2-C6烯基、C3-C6环烷基、芳基或杂芳基，其中任何含有烷基或环烷基的取代基都可以被一个或多个卤素取代，其条件是符合化学键与应变能的规则。The term aryl as used herein refers to substituted phenyl or naphthyl. The term heteroaryl refers to any 5- or 6-membered aromatic ring containing one or more heteroatoms; these heteroaromatic rings may also be fused with other aromatic systems. The above terms further encompass substituted or unsubstituted forms. The substituted form refers to being substituted by one or more groups, and the substituents are selected from nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio , C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 OC(O)alkyl, OC(O)aryl, C 3 -C 6 OC(O) Cycloalkyl, C 1 -C 6 NHC(O)alkyl, C 3 -C 6 NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, C 3 -C 6 Cyclo Alkylthio, C 3 -C 6 cycloalkylsulfonyl, C 3 -C 6 cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroaryl Sulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C ( O) RY , C(NOR X ) RY , wherein RY and R X are independently H, C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, aryl or heteroaryl, wherein any substituent containing alkyl or cycloalkyl can be substituted by one or more halogens, which The condition is that the rules of chemical bonds and strain energy are met.
本文所用的术语卤素和卤代包括氯、溴、氟和碘。术语卤代烷基等指的是被一个或多个卤原子取代的基团。As used herein, the terms halogen and halo include chlorine, bromine, fluorine and iodine. The terms haloalkyl and the like refer to groups substituted with one or more halogen atoms.
本文所用的术语Me指的是甲基。术语Et指的是乙基。术语Pr指的是丙基。术语Bu指的是丁基。术语Ph指的是苯基。术语EtOAc指的是乙酸乙酯。The term Me as used herein refers to methyl. The term Et refers to ethyl. The term Pr refers to propyl. The term Bu refers to butyl. The term Ph refers to phenyl. The term EtOAc refers to ethyl acetate.
本文所用的术语烷氧基指的是直链或支链烷氧基。术语卤代烷氧基指的是被一个或多个卤原子取代的烷氧基。The term alkoxy as used herein refers to straight or branched chain alkoxy. The term haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.
本文所用的术语杂原子指的是O、S和N。The term heteroatom as used herein refers to O, S and N.
优选的式
不言而喻，满足本文所给出的定义的化合物取代基的某些组合出于立体和/或化学的原因将是不可能制备的。本发明不包括这样的化合物。It goes without saying that certain combinations of substituents of compounds satisfying the definitions given herein will not be possible to prepare for steric and/or chemical reasons. The present invention does not include such compounds.
按常规方式可以制备式I化合物的各种水合物、盐和配合物。例如，用阳离子代替羟基氢原子(M＝H)可以生成盐，阳离子例如NH4+、+N(Bu)4、K+、Na+、Ca2+、Li+、Mg2+、Fe2+、Cu2+等。按照本发明，这些衍生物也是有用的。Various hydrates, salts and complexes of the compounds of formula I can be prepared in conventional manner. For example, salts can be formed by replacing hydroxyl hydrogen atoms (M=H) with cations such as NH 4+ , + N(Bu) 4 , K + , Na + , Ca 2+ , Li + , Mg 2+ , Fe 2+ , Cu 2+ and so on. These derivatives are also useful according to the invention.
本文全文中的所有温度均以摄氏度(℃)给出，所有百分比均为重量百分比，另有说明除外。术语ppm指的是百万分之浓度。术语psi指的是每平方英寸的磅数。术语m.p.指的是熔点。术语b.p.指的是沸点。All temperatures throughout this document are given in degrees Celsius (° C.) and all percentages are by weight unless otherwise indicated. The term ppm refers to parts per million concentration. The term psi refers to pounds per square inch. The term m.p. refers to melting point. The term b.p. refers to boiling point.
化合物的制备Preparation of compounds
本发明化合物是使用熟知的化学操作制备的。所需原料是商业上可得到的或者易于利用标准操作合成。The compounds of the present invention are prepared using well known chemical manipulations. The required starting materials are either commercially available or readily synthesized using standard procedures.
吡啶-2-甲酰胺的通用制备General preparation of pyridine-2-carboxamides
所需的HAA(2)是这样制备的，在一种偶联剂(光气或盐酸1-[3-二甲氨基丙基]-3-乙基碳二亚胺(EDCI)加1-羟基苯并三唑(HOBt)或1-羟基-7-氮杂苯并三唑(HOAt)和一种酸清除剂，例如N-甲基吗啉(NMM)、三乙胺、4-(二甲氨基)吡啶(DMAP)或二异丙基乙胺)的存在下，使适当的邻-羟基杂芳族羧酸(1)与一种胺反应(流程1)。在有些情况下，可以使具有被保护的羟基的酰氯、例如(3)与适当的胺反应，得到酰胺中间体(4)。在一种钯(Pd)催化剂的存在下经由氢化作用除去保护基团，得到所需产物(2X)。用酰基、磺酰基或甲硅烷基(M)封端化合物2中的杂环羟基可以这样实现，使用一种酰化催化剂，例如DMAP，在适合的溶剂中，例如吡啶，使适当的 2与羧酸酰氯、磺酰氯或甲硅烷基氯(MCl)反应，得到相应的O-酰基、O-磺酰基或O-甲硅烷基衍生物(2Y)。 The desired HAA (2) was prepared by adding 1-hydroxyl Benzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) and an acid scavenger such as N-methylmorpholine (NMM), triethylamine, 4-(dimethyl The appropriate ortho-hydroxyheteroaromatic carboxylic acid (1) is reacted with an amine in the presence of (amino)pyridine (DMAP) or diisopropylethylamine) (Scheme 1). In some cases, acid chlorides with protected hydroxyl groups, such as (3), can be reacted with appropriate amines to give amide intermediates (4). Removal of the protecting group via hydrogenation in the presence of a palladium (Pd) catalyst affords the desired product (2X). Capping the heterocyclic hydroxyl group in compound 2 with an acyl, sulfonyl or silyl group (M) can be achieved by reacting the appropriate 2 with the carboxylate using an acylation catalyst such as DMAP in a suitable solvent such as pyridine. Acid acid chloride, sulfonyl chloride or silyl chloride (MCl) is reacted to give the corresponding O-acyl, O-sulfonyl or O-silyl derivative (2Y).
邻-羟基杂芳族羧酸1的制备Preparation of o-hydroxyheteroaromatic carboxylic acid 1
羧酸1(X1＝N，X2＝X3＝CH，X4独立地是C-Me、C-SMe、C-Cl)的制备如流程2所示。在二甲基甲酰胺(DMF)-四氢呋喃(THF)的1∶1混合物中，使用叔丁醇钾作为碱，3-羟基-2-溴吡啶(5)与2-(三甲基甲硅烷基)乙氧基甲基氯(SEM-Cl)反应生成所需的醚6。用二异丙氨基化锂(LDA)进行 6的去质子化，然后与适当的亲电子试剂(碘代甲烷、二甲基二硫化物或六氯乙烷)缩合，得到4-取代的吡啶 7。在 7与正丁基锂(n-BuLi)之间进行溴/锂交换，然后用二氧化碳(CO2)进行羧基化，再进行酸水解，得到必需的4-取代的-3-羟基吡啶甲酸1X。 The preparation of carboxylic acid 1 (X 1 =N, X 2 =X 3 =CH, X 4 independently being C-Me, C-SMe, C-Cl) is shown in Scheme 2. In a 1:1 mixture of dimethylformamide (DMF)-tetrahydrofuran (THF), using potassium tert-butoxide as base, 3-hydroxy-2-bromopyridine (5) and 2-(trimethylsilyl ) ethoxymethyl chloride (SEM-Cl) to generate the desired ether 6. Deprotonation of 6 with lithium diisopropylamide (LDA), followed by condensation with an appropriate electrophile (methyl iodide, dimethyl disulfide, or hexachloroethane), afforded the 4-substituted pyridine 7 . Bromine/lithium exchange between 7 and n-butyllithium (n-BuLi), followed by carboxylation with carbon dioxide (CO 2 ) followed by acid hydrolysis affords the requisite 4-substituted-3-hydroxypicolinic acid 1X .
或者，3-羟基吡啶 (8)可以与SEM-Cl缩合，得到9(流程3)。用叔丁基锂(t-BuLi)进行 9的去质子化，然后与N-氟苯磺酰亚胺缩合，得到4-氟衍生物10。10与乙醇钠缩合，得到二醚11。用t-BuLi进行 11的去质子化，然后进行羧基化和酸水解，得到所需的4-乙氧基吡啶1X(X＝OEt)。 Alternatively, 3-hydroxypyridine (8) can be condensed with SEM-Cl to afford 9 (Scheme 3). Deprotonation of 9 with tert-butyllithium (t-BuLi) followed by condensation with N-fluorobenzenesulfonimide gave the 4-fluoroderivative 10. Condensation of 10 with sodium ethoxide gave diether 11. Deprotonation of 11 with t-BuLi followed by carboxylation and acid hydrolysis afforded the desired 4-ethoxypyridine 1X (X=OEt).
酰氯3的制备如流程4所述。因而，使用三氟化硼作为催化剂，在回流的甲醇中使3-羟基吡啶甲酸(12)转化为甲基酯13。然后在含水的碱中用溴溴化 13，得到二溴化物14。然后在氢化钠的存在下进行 14与苄基氯的缩合，制得苄基醚15。在甲醇/碳酸钾中小心地进行 15的甲醇分解，得到4-甲氧基吡啶甲酸衍生物16。使用苯溶剂和催化量的DMF，用草酰氯实现 16向酰氯3的转化。 The preparation of acid chloride 3 is described in Scheme 4. Thus, 3-hydroxypicolinic acid (12) was converted to methyl ester 13 in refluxing methanol using boron trifluoride as a catalyst. Bromination of 13 with bromine in aqueous base then affords the dibromide 14. Condensation of 14 with benzyl chloride in the presence of sodium hydride then afforded the benzyl ether 15. Careful methanolysis of 15 in methanol/potassium carbonate affords the 4-methoxypicolinic acid derivative 16. Conversion of 16 to acid chloride 3 was achieved with oxalyl chloride using benzene solvent and a catalytic amount of DMF.
4-乙氧基-3-羟基吡啶甲酸(1，X1＝N，X2＝X3＝CH，X4＝COEt)的制备(见流程1和3) Preparation of 4-ethoxy-3-hydroxypicolinic acid (1, X 1 =N, X 2 =X 3 =CH, X 4 =COEt) (see Schemes 1 and 3)
a. 3-(2-三甲基甲硅烷基)乙氧基甲氧基)吡啶(9)的制备a. Preparation of 3-(2-trimethylsilyl)ethoxymethoxy)pyridine (9)
向搅拌着的DMF(100ml)与THF(100ml)的混合物中加入固体叔丁醇钾(17.96g，0.16mol)。全部固体溶解后，将溶液冷却至≤5℃，一齐加入3-羟基吡啶(14.25g，0.15mol)。搅拌10分钟后，将混合物冷却至-10℃，以这样一种速率滴加SEM-Cl(25g，0.15mol)，使内部温度保持在≤-5℃。加入完全后，将混合物在0℃下搅拌1小时，然后在室温下搅拌2小时。将混合物倒在水(600ml)中，然后用乙醚萃取(3×150ml)。将乙醚萃取液合并，先后用2N NaOH(100ml)、水(50ml)和饱和NaCl溶液(100ml)洗涤，干燥(MgSO4)，浓缩，得到褐色液体。蒸馏得到所需的醚9，为无色液体(20.8g)，在0.03mmHg下b.p.95-99℃。To a stirred mixture of DMF (100 mL) and THF (100 mL) was added solid potassium tert-butoxide (17.96 g, 0.16 mol). After all the solids were dissolved, the solution was cooled to ≤5°C and 3-hydroxypyridine (14.25 g, 0.15 mol) was added all at once. After stirring for 10 minutes, the mixture was cooled to -10°C and SEM-Cl (25 g, 0.15 mol) was added dropwise at such a rate that the internal temperature was maintained at ≤ -5°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour and then at room temperature for 2 hours. The mixture was poured into water (600ml) and extracted with ether (3 x 150ml). The ether extracts were combined, washed successively with 2N NaOH (100ml), water (50ml) and saturated NaCl solution (100ml), dried ( MgSO4 ) and concentrated to give a brown liquid. Distillation afforded the desired ether 9 as a colorless liquid (20.8 g), bp 95-99°C at 0.03 mmHg.
b. 4-氟-3-(2-三甲基甲硅烷基)乙氧基甲氧基)吡啶(10)的制备b. Preparation of 4-fluoro-3-(2-trimethylsilyl)ethoxymethoxy)pyridine (10)
向在氩气氛下冷却至≤-70℃的搅拌着的 9(12.39g，0.055mol)的乙醚(200ml)溶液中缓慢加入t-BuLi(40ml，1.5M戊烷溶液)。在加入期间，使反应温度保持在≤-68℃。加入完全后，将混合物在≤-70℃下搅拌另外60分钟，然后经由套管转移至搅拌着的N-氟苯磺酰亚胺(18.92g)的无水THF(200ml)溶液中，后者也在氩下冷却至≤-70℃。加入完全后，除去冷水浴，使反应混合物温热至室温。加入水(100ml)，分离有机相，干燥(MgSO4)，浓缩，得到褐色的油。色谱纯化(硅胶，己烷-丙酮9∶1)得到所需产物 10，为橙色的油(7.5g)，含有约15％原料。该粗混合物直接用于下面的反应。To a stirred solution of 9 (12.39 g, 0.055 mol) in diethyl ether (200 ml) cooled to <-70°C under argon atmosphere was slowly added t-BuLi (40 ml, 1.5M in pentane). During the addition, the reaction temperature was maintained at <-68°C. After the addition was complete, the mixture was stirred at ≤-70°C for an additional 60 minutes, then transferred via cannula to a stirred solution of N-fluorobenzenesulfonimide (18.92 g) in anhydrous THF (200 ml), which Also cooled to <-70°C under argon. After the addition was complete, the cold water bath was removed and the reaction mixture was allowed to warm to room temperature. Water (100ml) was added and the organic phase was separated, dried ( MgSO4 ) and concentrated to give a brown oil. Chromatography (silica gel, hexane-acetone 9:1) gave the desired product 10 as an orange oil (7.5 g) containing about 15% starting material. This crude mixture was used directly in the next reaction.
c. 4-乙氧基-3-(2-三甲基甲硅烷基)乙氧基甲氧基)吡啶(11)的制备c. Preparation of 4-ethoxy-3-(2-trimethylsilyl)ethoxymethoxy)pyridine (11)
向搅拌着的乙醇钠(0.9g，13mmol)的乙醇(10ml)溶液中一齐加入10(1.07g，4.4mmol)。将所得混合物在室温下搅拌48小时，然后倒在水(100ml)中。所得混合物用乙醚萃取(3×50ml)。将乙醚萃取液合并，干燥(MgSO4)，浓缩。所得琥珀色油经过色谱纯化(硅胶，己烷-丙酮4∶1)得到 11，为黄色的油(0.6g)。To a stirred solution of sodium ethoxide (0.9 g, 13 mmol) in ethanol (10 mL) was added 10 (1.07 g, 4.4 mmol) all at once. The resulting mixture was stirred at room temperature for 48 hours, then poured into water (100ml). The resulting mixture was extracted with ether (3 x 50ml). The ether extracts were combined, dried ( MgSO4 ), and concentrated. The resulting amber oil was purified by chromatography (silica gel, hexane-acetone 4:1) to afford 11 as a yellow oil (0.6 g).
d. 4-乙氧基-3-羟基吡啶-2-羧酸(1，X1＝N，X2＝X3＝CH，X4＝COEt)d. 4-ethoxy-3-hydroxypyridine-2-carboxylic acid (1, X 1 =N, X 2 =X 3 =CH, X 4 =COEt)
将搅拌着的 11(2.9g)的THF(50ml)溶液在氩气氛下冷却至≤-70℃。向其中缓慢加入t-BuLi(8ml，1.5M戊烷溶液)，同时保持反应温度在≤-66℃。加入完全后，将混合物在≤-70℃下搅拌45分钟，然后倒在碎干冰的乙醚浆液中。搅拌所得混合物，直至达到室温，然后蒸发溶剂。向残余物中加入THF(25ml)和4N HCl(15ml)，将所得混合物在室温下搅拌2小时。搅拌结束时，过滤不溶性物质，用少量THF洗涤，风干，得到标题化合物，为白色固体(1.05g)。A stirred solution of 11 (2.9 g) in THF (50 ml) was cooled to <-70°C under argon atmosphere. To this was slowly added t-BuLi (8ml, 1.5M in pentane) while maintaining the reaction temperature at ≤ -66°C. After the addition was complete, the mixture was stirred at <-70°C for 45 minutes, then poured into a slurry of crushed dry ice in diethyl ether. The resulting mixture was stirred until reaching room temperature, then the solvent was evaporated. To the residue were added THF (25 ml) and 4N HCl (15 ml), and the resulting mixture was stirred at room temperature for 2 hr. At the end of stirring, the insoluble material was filtered, washed with a small amount of THF and air dried to give the title compound as a white solid (1.05g).
6-溴-3-苄氧基-4-甲氧基吡啶-2-羧酸(16)及其酰氯(3)的制备(见流程4) Preparation of 6-bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic acid (16) and its acid chloride (3) (see scheme 4)
a. 4，6-二溴-3-羟基吡啶-2-羧酸甲酯(14)的制备a. 4, the preparation of 6-dibromo-3-hydroxypyridine-2-carboxylate methyl ester (14)
向装有滴液漏斗和机械搅拌器的2L 3-颈烧瓶内加入水(800ml)和3-羟基吡啶-2-羧酸甲酯(15.3g)。向该搅拌着的溶液中缓慢加入溴(32 g)。随着反应的进行，有固体从溶液中分离出来，反应混合物变得难以搅拌。加入完全后，剧烈搅拌混合物，直至溴的颜色消失。少量粗产物样本的1H-NMR(CDCl3)显示，它是一溴产物与二溴产物的约3∶1混合物。向反应混合物中小心地加入碳酸钠(31.8g)，然后另外滴加溴(12g)。溴的颜色消失后，用浓HCl将反应混合物调至大约pH5，所得混合物用CH2Cl2萃取(3×150ml)。将有机萃取液合并，干燥(MgSO4)，浓缩，得到橙色固体(14g)。该物质(在木炭处理之后)能够从甲基环己烷中重结晶，得到 14，为白色固体，m.p.181-183℃。Water (800ml) and methyl 3-hydroxypyridine-2-carboxylate (15.3g) were added to a 2L 3-neck flask equipped with a dropping funnel and a mechanical stirrer. Bromine (32 g) was slowly added to the stirred solution. As the reaction progressed, solids separated out of solution and the reaction mixture became difficult to stir. After the addition was complete, the mixture was stirred vigorously until the bromine color disappeared. 1 H-NMR (CDCl 3 ) of a small sample of the crude product showed it to be an approximately 3:1 mixture of monobromo and dibromo products. Sodium carbonate (31.8 g) was carefully added to the reaction mixture, followed by additional dropwise addition of bromine (12 g). After the bromine color disappeared, the reaction mixture was adjusted to about pH 5 with concentrated HCl, and the resulting mixture was extracted with CH2Cl2 (3 x 150ml). The organic extracts were combined, dried ( MgSO4 ) and concentrated to give an orange solid (14g). This material (after charcoal treatment) could be recrystallized from methylcyclohexane to afford 14 as a white solid, mp 181-183°C.
b. 4，6-二溴-3-苄氧基吡啶-2-羧酸甲酯(15)的制备b. 4, the preparation of 6-dibromo-3-benzyloxypyridine-2-carboxylic acid methyl ester (15)
向搅拌着的氢化钠(0.6g)与DMF(50ml)的混合物中缓慢加入14(7.1g)。加入完全后，将混合物在室温下搅拌15分钟，然后一齐加入苄基氯(3.05g)。然后将混合物在90℃下加热六小时，冷却，倒在水(500ml)中，用乙醚萃取(2×200ml)。将乙醚萃取液合并，用2N NaOH(50ml)洗涤，干燥(MgSO4)，蒸发溶剂，得到 15，为浅黄色固体(8.3g)。从少量甲醇中重结晶，得到分析样本，m.p.75-76℃。To a stirred mixture of sodium hydride (0.6g) and DMF (50ml) was slowly added 14 (7.1g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90°C for six hours, cooled, poured into water (500ml) and extracted with ether (2x200ml). The ether extracts were combined, washed with 2N NaOH (50ml), dried ( MgSO4 ) and the solvent evaporated to afford 15 as a pale yellow solid (8.3g). Recrystallization from a small amount of methanol gave an analytical sample, mp 75-76°C.
c. 6-溴-3-苄氧基-4-甲氧基吡啶-2-羧酸(16)c. 6-bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic acid (16)
将剧烈搅拌着的 15(25.5g)、碳酸钾(75g)与甲醇(300ml)的混合物在回流下加热30小时。将混合物冷却，倒在水(800ml)中，加入浓HCl调至pH2。所得混合物用CH2Cl2萃取(3×150ml)。将有机萃取液合并，干燥(MgSO4)，蒸发溶剂，得到几乎无色的油(20.5g)，放置后缓慢固化。从甲醇(125ml)/水(40ml)中重结晶，得到所需的酸16(11.6g)，m.p.134-135℃。A vigorously stirred mixture of 15 (25.5g), potassium carbonate (75g) and methanol (300ml) was heated at reflux for 30 hours. The mixture was cooled, poured into water (800ml) and adjusted to pH 2 by addition of concentrated HCl. The resulting mixture was extracted with CH2Cl2 (3 x 150ml). The organic extracts were combined, dried ( MgSO4 ) and the solvent evaporated to give an almost colorless oil (20.5g) which slowly solidified on standing. Recrystallization from methanol (125ml)/water (40ml) afforded the desired acid 16 (11.6g), mp 134-135°C.
d. 6-溴-3-苄氧基-4-甲氧基吡啶-2-碳酰氯(3)的制备d. Preparation of 6-bromo-3-benzyloxy-4-methoxypyridine-2-carbonyl chloride (3)
向搅拌着的 16(2.54g，7.5mmol)与含有DMF(3滴)的苯(30ml)的混合物中一齐加入草酰氯(1.90g，15mmol)。气体放出停止(约45分钟)后，将现已均匀的溶液搅拌另外15分钟，然后蒸发溶剂。加入1，2-二氯乙烷(30ml)，再次蒸发溶剂，得到定量收率的 3，为几乎无色的油。将该物质溶于CH2Cl2(10ml)或THF(10ml)，直接用于随后的偶联反应。To a stirred mixture of 16 (2.54 g, 7.5 mmol) and benzene (30 mL) containing DMF (3 drops) was added oxalyl chloride (1.90 g, 15 mmol) all at once. After gas evolution had ceased (approximately 45 minutes), the now homogenous solution was stirred for an additional 15 minutes before the solvent was evaporated. 1,2-Dichloroethane (30ml) was added and the solvent evaporated again to give 3 in quantitative yield as an almost colorless oil. This material was dissolved in CH2Cl2 ( 10ml ) or THF (10ml) and used directly in the subsequent coupling reaction.
6-溴-3-羟基吡啶甲酸(17) 6-Bromo-3-hydroxypicolinic acid (17)
历时30分钟，向机械搅拌着的3-羟基吡啶甲酸甲酯(30.6g)的水(800ml)溶液中缓慢加入溴(32g)。加入完全后，继续搅拌一小时。加入乙醚(300ml)，继续搅拌，直至全部固体溶解。分离有机层，含水相用乙醚(200ml)萃取。将有机相合并，干燥(MgSO4)，蒸发溶剂，得到32.8g 6-溴-3-羟基吡啶甲酸甲酯，为不完全白色固体。从甲醇/水中重结晶，得到分析样本，m.p.115-117℃。To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6g) in water (800ml) was slowly added bromine (32g) over a period of 30 minutes. After the addition was complete, stirring was continued for one hour. Diethyl ether (300ml) was added and stirring continued until all solids had dissolved. The organic layer was separated and the aqueous phase was extracted with diethyl ether (200ml). The organic phases were combined, dried ( MgSO4 ) and the solvent was evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, mp 115-117°C.
向搅拌着的该酯(2.32g)的THF(15ml)溶液中一齐加入LiOH.H2O(1g)的水(7ml)溶液。将所得混合物在室温下搅拌2小时，然后倒在水(100ml)中。用1N HCl调至大约pH3，混合物然后用CH2Cl2萃取(3×100ml)。将有机萃取液干燥(MgSO4)，过滤，浓缩，得到2.0g白色固体，其1H-NMR和MS与所需的标题酸 17是一致的。To a stirred solution of the ester (2.32g) in THF (15ml) was added LiOH.H2O (1g) in water (7ml) all at once. The resulting mixture was stirred at room temperature for 2 hours, then poured into water (100ml). Adjusted to approximately pH 3 with 1N HCl, the mixture was then extracted with CH2Cl2 (3 x 100ml). The organic extracts were dried ( MgSO4 ), filtered and concentrated to afford 2.0 g of a white solid whose1H -NMR and MS were consistent with the desired title acid 17 .
3-苄氧基-6-甲氧基吡啶甲酸(18) 3-Benzyloxy-6-methoxypicolinic acid (18)
将3-苄氧基吡啶甲酸甲酯(4.86g)与3-氯过苯甲酸(5.75g，60％过酸)的CH2Cl2(100ml)溶液在室温下搅拌40小时。反应混合物然后用5％亚硫酸氢钠溶液(100ml)萃取，然后用0.5N NaOH溶液(150ml)萃取。干燥(MgSO4)后，蒸发溶剂，得到4.9g 3-苄氧基吡啶甲酸甲酯-1-氧化物，为白色固体。从甲基环己烷/甲苯中重结晶，得到结晶性固体，m.p.104-106℃。A solution of methyl 3-benzyloxypicolinate (4.86g) and 3-chloroperbenzoic acid (5.75g, 60% peracid) in CH2Cl2 ( 100ml ) was stirred at room temperature for 40 hours. The reaction mixture was then extracted with 5% sodium bisulfite solution (100ml) followed by 0.5N NaOH solution (150ml). After drying ( MgSO4 ), the solvent was evaporated to give 4.9 g of methyl 3-benzyloxypicolinate-1-oxide as a white solid. Recrystallization from methylcyclohexane/toluene gave a crystalline solid, mp 104-106°C.
将该化合物(16.1g)的乙酸酐(80ml)溶液在125℃油浴中搅拌加热3小时。在旋转蒸发器上除去过量乙酸酐，将残余物溶于甲醇(200ml)。加入浓硫酸(1ml)，将所得混合物在回流下加热90分钟。蒸发溶剂，然后向残余物中加入饱和碳酸氢钠。所得混合物用CH2Cl2萃取(3×100ml)。将有机部分合并，干燥(MgSO4)，蒸发溶剂，得到15.5g 3-苄氧基-6-羟基吡啶甲酸甲酯，为黄色固体。从甲苯中重结晶，得到淡黄色固体，m.p.91-92℃。A solution of this compound (16.1 g) in acetic anhydride (80 ml) was stirred and heated in an oil bath at 125°C for 3 hours. Excess acetic anhydride was removed on a rotary evaporator and the residue was dissolved in methanol (200ml). Concentrated sulfuric acid (1 ml) was added and the resulting mixture was heated at reflux for 90 minutes. The solvent was evaporated, and saturated sodium bicarbonate was added to the residue. The resulting mixture was extracted with CH2Cl2 (3 x 100ml). The organic fractions were combined, dried ( MgSO4 ) and the solvent was evaporated to give 15.5 g of methyl 3-benzyloxy-6-hydroxypicolinate as a yellow solid. Recrystallization from toluene gave a pale yellow solid, mp 91-92°C.
向在60℃油浴中加热的搅拌着的该化合物(10.25g)的甲苯(125ml)溶液中加入碳酸银(16.6g)，然后加入甲基碘(8.52g)。将所得混合物在60℃下搅拌加热3小时。冷却后，通过C盐过滤混合物，蒸发溶剂，得到黄色的油。硅胶色谱纯化(4∶1己烷/丙酮)得到几乎无色的油，其1H-NMR和MS数据与3-苄氧基-6-甲氧基吡啶甲酸甲酯是一致的。如上有关酯所述用LiOH.H2O实现该酯向标题酸18的水解。To a stirred solution of this compound (10.25 g) in toluene (125 ml) heated in an oil bath at 60°C were added silver carbonate (16.6 g) followed by methyl iodide (8.52 g). The resulting mixture was stirred and heated at 60°C for 3 hours. After cooling, the mixture was filtered through Celite® and the solvent was evaporated to give a yellow oil. Chromatography on silica gel (4: 1 hexane/acetone) afforded a nearly colorless oil whose1H-NMR and MS data were consistent with methyl 3-benzyloxy-6-methoxypicolinate. Hydrolysis of the ester to the title acid 18 was accomplished with LiOH.H2O as described above for the ester.
4-羟基嘧啶-5-羧酸(19)
按照M.Pesson等《欧洲医药化学杂志-Chim.Ther.》1974，9，585的操作可以制备4-羟基嘧啶-5-羧酸乙酯。将该酯(500mg，3mmol)的THF(10ml)与MeOH(5ml)溶液用LiOH.H2O(373mg，8.9mmol)处理，搅拌过夜。用浓HCl(1ml)猝灭混合物，用EtOAc萃取(2×20ml)。将合并后的有机萃取液干燥(MgSO4)，浓缩，得到260mg标题化合物19，为橙色固体，m.p.220℃(分解)。4-羟基-2-甲基嘧啶-5-羧酸(20)
按照Geissman等《有机化学杂志》1946，11，741的操作可以制备4-羟基-2-甲基嘧啶-5-羧酸乙酯。将该酯(750mg，4.11mmol)的THF(10ml)与MeOH(5ml)溶液用LiOH.H2O(431mg，10.3mmol)处理，搅拌过夜。用浓HCl(1ml)猝灭混合物，用EtOAc萃取(2×20ml)。将合并后的有机萃取液干燥(MgSO4)，浓缩，得到155mg标题化合物 20，为白色固体，m.p.180℃(分解)。4-Hydroxy-2-methylpyrimidine-5-carboxylic acid ethyl ester can be prepared according to the operation of Geissman et al. "Journal of Organic Chemistry" 1946, 11, 741. A solution of the ester (750mg, 4.11mmol) in THF (10ml) and MeOH (5ml) was treated with LiOH.H2O (431mg, 10.3mmol) and stirred overnight. The mixture was quenched with cone. HCl (1 ml) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were dried ( MgSO4 ) and concentrated to afford 155 mg of the title compound 20 as a white solid, mp 180°C (dec).
5，6-二氯-3-羟基吡嗪-2-羧酸(21) 5,6-Dichloro-3-hydroxypyrazine-2-carboxylic acid (21)
将3-氨基-5，6-二氯吡嗪-2-羧酸甲酯(5.0g，23mmol)在浓硫酸(140ml)中搅拌，冷却至0℃。缓慢加入亚硝酸钠，保持温度在0℃左右。在0℃下经过30分钟后，使混合物温热至环境温度，搅拌3小时。将混合物倒在500g冰中，导致起泡和发泡。30分钟后，混合物用EtOAc萃取3次。将合并后的有机萃取液干燥(MgSO4)，过滤，浓缩。将残留黄色固体用水洗涤，风干，得到5.0g黄色固体，m.p.114-116℃，其13C-NMR光谱与标题化合物的甲基酯是一致的。Stir methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) in concentrated sulfuric acid (140 ml), and cool to 0°C. Add sodium nitrite slowly, keeping the temperature at around 0°C. After 30 minutes at 0°C, the mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was poured over 500g of ice, causing foaming and foaming. After 30 minutes, the mixture was extracted 3 times with EtOAc. The combined organic extracts were dried ( MgSO4 ), filtered and concentrated. The residual yellow solid was washed with water and air-dried to obtain 5.0 g of yellow solid, mp 114-116°C, whose 13 C-NMR spectrum was consistent with the methyl ester of the title compound.
将该固体(5.0g)用1N NaOH(20ml)处理，将混合物在90℃下加热1.5小时。冷却后，混合物用浓HCl酸化，用EtOAc萃取3次。干燥(MgSO4)，过滤，浓缩，得到0.48g深黄色固体，其1H-NMR和MS光谱与标题酸 21是一致的。The solid (5.0 g) was treated with 1 N NaOH (20 ml) and the mixture was heated at 90°C for 1.5 hours. After cooling, the mixture was acidified with concentrated HCl and extracted 3 times with EtOAc. Drying ( MgSO4 ), filtration and concentration afforded 0.48 g of a dark yellow solid whose 1 H-NMR and MS spectra were consistent with the title acid 21 .
6-氯-3-羟基-5-甲氧基吡嗪-2-羧酸(22)
将搅拌着的3-氨基-5，6-二氯吡嗪-2-羧酸甲酯(5.0g，23mmol)与甲醇钠(3.6g，67.5mmol)在绝对MeOH(50ml)中的混合物在回流下加热2小时，然后冷却，用浓HCl酸化。过滤收集沉淀，用水洗涤，风干，得到3.6g褐色固体。从己烷-EtOAc(1∶1)中重结晶，得到2.6g淡黄色固体，其光谱与3-氨基-6-氯-5-甲氧基吡嗪-2-羧酸甲酯是一致的。A stirred mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) and sodium methoxide (3.6 g, 67.5 mmol) in absolute MeOH (50 ml) was refluxed It was heated at lower temperature for 2 hours, then cooled and acidified with conc. HCl. The precipitate was collected by filtration, washed with water, and air-dried to obtain 3.6 g of a brown solid. Recrystallization from hexane-EtOAc (1:1) gave 2.6 g of a pale yellow solid whose spectrum was consistent with methyl 3-amino-6-chloro-5-methoxypyrazine-2-carboxylate.
将该化合物(1g，4.6mmol)溶于浓硫酸，冷却至0℃，缓慢用亚硝酸钠(0.5g，6.9mmol)处理。在0℃下30分钟后，将混合物倒在300g冰/水中，导致发泡。继续搅拌30分钟，然后过滤收集固体，用水洗涤。将湿固体溶于EtOAc，干燥(MgSO4)，过滤，浓缩。得到0.95g不完全白色固体，m.p.180-182℃，其NMR光谱与6-氯-3-羟基-5-甲氧基吡嗪-2-羧酸甲酯是一致的。This compound (1 g, 4.6 mmol) was dissolved in concentrated sulfuric acid, cooled to 0°C, and slowly treated with sodium nitrite (0.5 g, 6.9 mmol). After 30 minutes at 0°C, the mixture was poured on 300 g ice/water, resulting in foaming. Stirring was continued for 30 minutes, then the solid was collected by filtration and washed with water. The wet solid was dissolved in EtOAc, dried ( MgSO4 ), filtered and concentrated. This gave 0.95 g of a partially white solid, mp 180-182°C, whose NMR spectrum was consistent with methyl 6-chloro-3-hydroxy-5-methoxypyrazine-2-carboxylate.
将该固体(0.9g，4.1mmol)用1N NaOH(60ml)处理，将混合物搅拌1小时，然后用浓HCl酸化。过滤收集沉淀，用水洗涤，然后溶于EtOAc，干燥(MgSO4)，过滤，浓缩。得到0.62g淡黄色固体，m.p.170-173℃，其光谱与所需标题酸22是一致的。The solid (0.9g, 4.1mmol) was treated with 1N NaOH (60ml), the mixture was stirred for 1 hour and then acidified with concentrated HCl. The precipitate was collected by filtration, washed with water, then dissolved in EtOAc, dried ( MgSO4 ), filtered and concentrated. This gave 0.62 g of a pale yellow solid, mp 170-173°C, whose spectrum was consistent with the desired title acid 22.
4-羟基异噻唑-3-羧酸(23)4-Hydroxyisothiazole-3-carboxylic acid (23)
按照流程5所示操作得到该酸。 The acid was obtained by working as shown in Scheme 5.
因而，在用氮冲洗的烧瓶内，向搅拌着的固体KOH(88％，6.98g，0.11mol)的75ml EtOH溶液中加入用25ml EtOH洗涤过的硫羟乙酸(8.36g，0.11mol)。在带有塞子的烧瓶内将混合物在氮下搅拌5分钟。向其中加入0.1mol粗溴化合物(按照M.Hatanaka和T.Ishimaru《医药化学杂志》1973，16，798新鲜制备)。用氮冲洗烧瓶，盖上塞子。将混合物在环境水浴中搅拌3小时，然后倒在300ml CH2Cl2和1000ml水中。含水层用200ml CH2Cl2萃取四次。将合并后的有机萃取液用100ml冷水和饱和盐溶液洗涤，干燥。将粗化合物过滤，浓缩。所得的油经过硅胶色谱纯化，用二乙醚作为洗脱剂，得到13g浅黄色油，放置后固化形成胶状固体。光谱数据与2-乙酰氨基-4-乙酰硫基-3-氧代丁酸乙酯是一致的。Thus, to a stirred solution of solid KOH (88%, 6.98 g, 0.11 mol) in 75 mL EtOH in a nitrogen flushed flask was added thiolacetic acid (8.36 g, 0.11 mol) washed with 25 mL EtOH. The mixture was stirred under nitrogen in a stoppered flask for 5 minutes. To this was added 0.1 mol of crude bromine compound (freshly prepared according to M. Hatanaka and T. Ishimaru "Journal of Medicinal Chemistry" 1973, 16, 798). The flask was flushed with nitrogen and stoppered. The mixture was stirred for 3 hours in an ambient water bath, then poured into 300ml CH2Cl2 and 1000ml water. The aqueous layer was extracted four times with 200 ml CH2Cl2 . The combined organic extracts were washed with 100 ml of cold water and saturated saline solution, and dried. The crude compound was filtered and concentrated. The resulting oil was chromatographed on silica gel using diethyl ether as eluent to give 13 g of a pale yellow oil which solidified on standing to form a gummy solid. Spectral data were consistent with ethyl 2-acetylamino-4-acetylthio-3-oxobutanoate.
历时45分钟，向在冰浴中冷却至5℃以下的迅速搅拌着的该化合物(12.95g)的450ml氯仿溶液中滴加溴(15.8g，2当量)的50ml氯仿溶液。继续在冰浴中搅拌45分钟，然后在环境温度下搅拌30小时。混合物然后用200ml水洗涤，然后用另100ml水洗涤。将合并后的水洗液用100ml氯仿反萃取。将合并后的氯仿溶液用饱和盐溶液洗涤，经MgSO4干燥。将溶液过滤，浓缩至粗的油。经过硅胶色谱纯化，用石油醚-CH2Cl2(3∶1)至CH2Cl2的连续梯度洗脱，先得到0.79g 5-溴-4-羟基异噻唑-3-羧酸乙酯，再得到3.40g 4-羟基异噻唑-3-羧酸乙酯，为无色晶体，m.p.44-47℃，MS和1H-NMR是一致的。To a rapidly stirred solution of this compound (12.95 g) in 450 mL of chloroform cooled in an ice bath to below 5°C was added dropwise a solution of bromine (15.8 g, 2 equiv) in 50 mL of chloroform over 45 minutes. Stirring was continued for 45 minutes in the ice bath, then for 30 hours at ambient temperature. The mixture was then washed with 200ml of water and then with another 100ml of water. The combined water washes were back extracted with 100 ml of chloroform. The combined chloroform solution was washed with saturated saline solution and dried over MgSO 4 . The solution was filtered and concentrated to a crude oil. Purification by silica gel chromatography, eluting with a continuous gradient of petroleum ether-CH 2 Cl 2 (3:1) to CH 2 Cl 2 , first gave 0.79 g of ethyl 5-bromo-4-hydroxyisothiazole-3-carboxylate, Another 3.40 g of ethyl 4-hydroxyisothiazole-3-carboxylate was obtained as colorless crystals, mp44-47°C, MS and 1 H-NMR were consistent.
向710mg后者酯的30ml THF溶液中加入370mg LiOH.H2O(2.2当量)的10ml水溶液。将混合物在环境温度下搅拌3小时，然后在冰箱内冷却。过滤收集所沉淀的固体，得到710mg羧酸的二锂盐。将该盐溶于7ml水，在冰浴中冷却，加入2N HCl调至pH1。所得溶液用50ml EtOAc萃取三次。将合并后的萃取液用5ml盐水洗涤，干燥(Na2SO4)，过滤，将滤液置于冰箱内。将冷却后的溶液重新过滤，浓缩滤液，得到230mg无色固体，m.p.185-89℃，其1H-NMR和13C-NMR光谱与标题化合物23是一致的。To a solution of 710 mg of the latter ester in 30 ml of THF was added 370 mg of LiOH.H2O (2.2 equivalents) in 10 ml of water. The mixture was stirred at ambient temperature for 3 hours, then cooled in the refrigerator. The precipitated solid was collected by filtration to obtain 710 mg of the dilithium salt of the carboxylic acid. The salt was dissolved in 7 ml of water, cooled in an ice bath, and adjusted to pH 1 by adding 2N HCl. The resulting solution was extracted three times with 50 ml EtOAc. The combined extracts were washed with 5 ml of brine, dried ( Na2SO4 ), filtered, and the filtrate was placed in a refrigerator. The cooled solution was re-filtered, and the filtrate was concentrated to obtain 230 mg of a colorless solid, mp 185-89°C, whose 1 H-NMR and 13 C-NMR spectra were consistent with the title compound 23.
3-苄氧基-1-甲基吡唑-4-羧酸(24)和5-苄氧基-1-甲基吡唑-4-羧酸(25)
按照S.Yamamoto等日本专利JP 62148482，1987的操作，使3-羟基-1-甲基吡唑-4-羧酸乙酯与5-羟基-1-甲基吡唑-4-羧酸乙酯的混合物(通过Y.Wang等《浙江工学院学报》1994，2，67的操作得到)苄基化，通过柱色谱法分离混合物，用3∶1己烷∶EtOAc作为洗脱剂，得到3-苄氧基-1-甲基吡唑-4-羧酸乙酯和5-苄氧基-1-甲基吡唑-4-羧酸乙酯，1H-NMR测定它们是纯的。According to Japanese patent JP 62148482 such as S.Yamamoto, the operation of 1987, make 3-hydroxyl-1-methylpyrazole-4-carboxylic acid ethyl ester and 5-hydroxyl-1-methylpyrazole-4-carboxylic acid ethyl ester The mixture (obtained by the operation of Y.Wang et al. "Journal of Zhejiang Institute of Technology" 1994, 2, 67) was benzylated, and the mixture was separated by column chromatography, using 3:1 hexane:EtOAc as eluent to give 3- Benzyloxy-1-methylpyrazole-4-carboxylic acid ethyl ester and 5-benzyloxy-1-methylpyrazole-4-carboxylic acid ethyl ester were pure as determined by 1 H-NMR.
将3-苄氧基-1-甲基吡唑-4-羧酸乙酯(283mg，1.08mmol)的THF(10ml)、MeOH(2ml)与水(5ml)溶液用LiOH.H2O(91mg，2.17mmol)处理，搅拌过夜。用浓HCl(1ml)猝灭混合物，用EtOAc萃取(2×20ml)。将合并后的有机层干燥(MgSO4)，浓缩，得到白色固体(227mg)，m.p.169-172℃，其光谱与3-苄氧基-1-甲基吡唑-4-羧酸(24)是一致的。A solution of ethyl 3-benzyloxy-1-methylpyrazole-4-carboxylate (283 mg, 1.08 mmol) in THF (10 ml), MeOH (2 ml) and water (5 ml) was dissolved in LiOH.H 2 O (91 mg , 2.17mmol) and stirred overnight. The mixture was quenched with cone. HCl (1 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layers were dried (MgSO 4 ) and concentrated to give a white solid (227 mg), mp 169-172°C, whose spectrum matched that of 3-benzyloxy-1-methylpyrazole-4-carboxylic acid (24) consistent.
同样将5-苄氧基-1-甲基吡唑-4-羧酸乙酯(755mg，2.9mmol)在THF(20ml)、MeOH(4ml)与水(10ml)中用LiOH.H2O(243mg，5.8mmol)水解，得到608mg 5-苄氧基-1-甲基吡唑-4-羧酸(25)，为白色固体，m.p.117-122℃。Similarly ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate (755 mg, 2.9 mmol) in THF (20 ml), MeOH (4 ml) and water (10 ml) was dissolved in LiOH.H 2 O ( 243 mg, 5.8 mmol) were hydrolyzed to give 608 mg of 5-benzyloxy-1-methylpyrazole-4-carboxylic acid (25) as a white solid, mp 117-122°C.
其他杂芳族羧酸的制备Preparation of other heteroaromatic carboxylic acids
通过M.Mittelbach等《药学文献》(Weinheim，Germany)1985，318，481-486的操作制备4-羟基烟酸。按照A.Dornow《化学报告》1940，73，153的方法可以制备2-羟基-6-甲基烟酸。按照R.Mariella和E.Belcher《美国化学会志》1951，73，2616的方法可以制备4，6-二甲基-2-羟基烟酸。通过A.Cale等《医药化学杂志》1989，32，2178的操作可以制备5-氯-2-羟基-6-甲基烟酸。通过P.Nantka-Namirski和A Rykowski《化学文摘》1972，77，114205的方法可以制备2，5-二羟基烟酸。按照J.D.Crum和C.H.Fuchsman《杂环化学杂志》1966，3，252-256的方法制备3-羟基异烟酸。按照A.P.Krapcho等《杂环化学杂志》1997，34，27的方法可以制备3-羟基吡嗪-2-羧酸。通过相应的乙基酯的水解可以制备5，6-二甲基-3-羟基吡嗪-2-羧酸，其合成描述在S.I.Zavyalov和A.G.Zavozin《Izv.Akad.Nauk SSSR》1980，(5)，1067-1070中。通过I.Ichimoto，K.Fujii和C.Tatsumi《农业生物化学》1967，31，979的方法制备4-羟基哒嗪-3-羧酸。通过E.Falco，E.Pappas和G.Hitchings《美国化学会志》1956，78，1938的方法制备3，5-二羟基-1，2，4-三嗪-6-羧酸。按照R.Barlow和A.Welch《美国化学会志》1956，78，1258的方法制备5-羟基-3-甲硫基-1，2，4-三嗪-6-羧酸。通过T.M.Willson等《生物有机与医药化学快报》1996，6，1043的方法制备羟基异噻唑-、羟基异噁唑-和羟基吡唑-羧酸。通过J.M.Ross等《美国化学会志》1964，86，2861的方法制备3-羟基-1，2，5-噻二唑-4-羧酸。按照K.Bowden等《英国化学会志》(C)，1968，172所述操作得到3-羟基异噁唑-4-羧酸。按照A.W.Taylor和R.T.Cook《四面体》1987，43，607的方法生成3-羟基-1-苯基吡唑-4-羧酸酯。按照D.L.Boger和J.H.Chen《有机化学杂志》1995，60，7369-7371的操作制备3-苄氧基喹啉-2-羧酸。4-Hydroxynicotinic acid was prepared by the procedure of M. Mittelbach et al., Weinheim, Germany 1985, 318, 481-486. According to the method of A. Dornow "Chemical Reports" 1940, 73, 153, 2-hydroxy-6-methylnicotinic acid can be prepared. According to the method of R.Mariella and E.Belcher "Journal of the American Chemical Society" 1951, 73, 2616, 4,6-dimethyl-2-hydroxynicotinic acid can be prepared. 5-Chloro-2-hydroxy-6-methylnicotinic acid can be prepared by the operation of A. Cale et al. "Journal of Medicinal Chemistry" 1989, 32, 2178. 2,5-dihydroxynicotinic acid can be prepared by the method of P. Nantka-Namirski and A Rykowski "Chemical Abstracts" 1972, 77, 114205. 3-Hydroxyisonicotinic acid was prepared according to the method of J.D. Crum and C.H. Fuchsman, Journal of Heterocyclic Chemistry, 1966, 3, 252-256. 3-Hydroxypyrazine-2-carboxylic acid can be prepared according to the method of A.P. Krapcho et al. "Journal of Heterocyclic Chemistry" 1997, 34, 27. 5,6-Dimethyl-3-hydroxypyrazine-2-carboxylic acid can be prepared by hydrolysis of the corresponding ethyl ester, the synthesis of which is described in S.I.Zavyalov and A.G.Zavozin "Izv.Akad.Nauk SSSR" 1980, (5 ), 1067-1070. 4-Hydroxypyridazine-3-carboxylic acid was prepared by the method of I. Ichimoto, K. Fujii and C. Tatsumi "Agricultural Biochemistry" 1967, 31, 979. 3,5-Dihydroxy-1,2,4-triazine-6-carboxylic acid was prepared by the method of E. Falco, E. Pappas and G. Hitchings J. American Chemical Society 1956, 78, 1938. 5-Hydroxy-3-methylthio-1,2,4-triazine-6-carboxylic acid was prepared according to the method of R. Barlow and A. Welch, J. American Chemical Society, 1956, 78, 1258. Hydroxyisothiazole-, hydroxyisoxazole- and hydroxypyrazole-carboxylic acids were prepared by the method of T.M.Willson et al. Bioorganic and Medicinal Chemistry Letters 1996, 6, 1043. 3-Hydroxy-1,2,5-thiadiazole-4-carboxylic acid was prepared by the method of J.M. Ross et al. 3-Hydroxyisoxazole-4-carboxylic acid was obtained according to the operation described in K. Bowden et al. "Journal of the British Chemical Society" (C), 1968, 172. 3-Hydroxy-1-phenylpyrazole-4-carboxylate was formed following the procedure of A.W. Taylor and R.T. Cook Tetrahedron 1987, 43, 607. 3-Benzyloxyquinoline-2-carboxylic acid was prepared according to the procedure of D.L. Boger and J.H. Chen "Journal of Organic Chemistry" 1995, 60, 7369-7371.
胺与苯胺中间体的通用制备General preparation of amine and aniline intermediates
利用金属氢化物或者溶解金属的反应还原相应的肟，进行环状、无环族与苄基胺的合成，参见R.O.Hutchins和M.K.Hutchins《综合有机合成》；B.M.Trost，Ed.；Pergamon Press：Oxford，1991；Vol.8，p.65；或J.W.Huffman《综合有机合成》；B.M.Trost，Ed.；Pergamon Press：Oxford，1991；Vol.8，p.124。或者，可以从必要的酮和醛经由洛伊卡特反应直接制备这些胺，参见R.Carlson，T.Lejon，T.Lunstedt和E.LeClouerec《斯堪的纳维亚化学学报》1993，47，1046。苯胺一般是这样制备的，使用披钯碳或硫化披钯碳作为催化剂进行相应的硝基芳族化合物的催化还原。这样的操作已有文献详细记载，例如R.L.Augustine《催化氢化》MarcelDecker，Inc.，New York，1965。Synthesis of cyclic, acyclic, and benzylamines by reduction of the corresponding oximes by metal hydrides or reactions of dissolved metals, see R.O. Hutchins and M.K. Hutchins, General Organic Synthesis; B.M.Trost, Ed.; Pergamon Press: Oxford , 1991; Vol.8, p.65; or J.W.Huffman "Comprehensive Organic Synthesis"; B.M.Trost, Ed.; Pergamon Press: Oxford, 1991; Vol.8, p.124. Alternatively, these amines can be prepared directly from the necessary ketones and aldehydes via the Leukart reaction, see R. Carlson, T. Lejon, T. Lunstedt and E. LeClouerec Scandinavian Acta Chemie 1993, 47, 1046 . Anilines are generally prepared by catalytic reduction of the corresponding nitroaromatics using palladium on carbon or palladium sulfide on carbon as catalyst. Such operations are well documented in the literature, for example R.L. Augustine "Catalytic Hydrogenation" Marcel Decker, Inc., New York, 1965.
按照M.Shimano，N.Kamei，T.Shibata，K.Inoguchi，N.Itoh，T.Ikari和H.Senda《四面体》1998，54，12745的操作或其改进操作制备胺49，它是9元二内酯环系。这样一种改进操作如流程6所示。因而，用硼氢化锂还原
26(见上述参考文献)，用三异丙基硅烷(TIPS)封端所得伯醇，得到
27。使
27的游离羟基与1-溴-2-甲基-2-丙烯反应，然后进行双键的催化还原，得到
28。选择性除去对-甲氧基苄基(PMB)保护基团，然后与N-t-BOC-O-苄基-L-丝氨酸缩合，得到
29。除去TIPS基团，然后氧化所得羟基，得到
30。随后利用上述参考文献所述操作将该物质(30)转化为胺
31。
以相似的方式，流程7和8分别概述了缺乏环外酯官能团的氨基二内酯 38和 48的合成。 In a similar manner, Schemes 7 and 8 outline the synthesis of aminodilactones 38 and 48 , respectively, lacking exocyclic ester functionality.
27的制备(见流程6)The preparation of 27 (see scheme 6)
向硼氢化锂的7.5ml无水THF溶液(2.0M，7.5ml，15mmol)中加入0.1ml硼酸三甲酯。将该混合物在氮气氛下冷却至-30℃。历时10分钟向该溶液中滴加化合物26(4.58g，10mmol)的10ml THF溶液。将溶液在-30℃下搅拌1小时，然后在0℃下搅拌5小时。滴加饱和氯化铵溶液(10ml)，将混合物搅拌10分钟，分离各相。含水相用EtOAc萃取(2×25ml)，将合并后的有机相用饱和盐水洗涤，经硫酸钠干燥，蒸发至干。粗产物经过色谱纯化，得到2.1g白色固体。样本从己烷-EtOAc中重结晶，得到微细白色针晶，m.p.91-93℃，[α]D 25＝+31.9°(C＝1.04，CHCl3)。将该二醇(2.04g，6.22mmol)溶于4ml无水DMF，加入咪唑(680mg，10mmol)。将溶液在冰浴中冷却，然后历时2分钟加入三异丙基氯代硅烷(1.39ml，6.5mmol)。将混合物在室温下搅拌4小时，然后倒在冰水中，用20％乙醚的己烷溶液萃取(3×15ml)。将合并后的有机相用盐水洗涤，干燥，通过短硅胶塞过滤，用20ml相同溶剂洗涤。蒸发溶剂，得到2.77g化合物27，为苍白色粘性油，1H-NMR证实是非常纯的。To a solution of lithium borohydride in 7.5 ml of anhydrous THF (2.0 M, 7.5 ml, 15 mmol) was added 0.1 ml of trimethyl borate. The mixture was cooled to -30°C under nitrogen atmosphere. To this solution was added dropwise a solution of compound 26 (4.58 g, 10 mmol) in 10 ml THF over 10 minutes. The solution was stirred at -30°C for 1 hour, then at 0°C for 5 hours. Saturated ammonium chloride solution (10ml) was added dropwise, the mixture was stirred for 10 minutes and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 25ml) and the combined organic phases were washed with saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by chromatography to yield 2.1 g of a white solid. A sample was recrystallized from hexane-EtOAc to give fine white needles, mp 91-93°C, [α] D 25 =+31.9° (C=1.04, CHCl 3 ). The diol (2.04g, 6.22mmol) was dissolved in 4ml dry DMF and imidazole (680mg, 10mmol) was added. The solution was cooled in an ice bath, then triisopropylchlorosilane (1.39ml, 6.5mmol) was added over 2 minutes. The mixture was stirred at room temperature for 4 hours, then poured into ice water and extracted with 20% diethyl ether in hexane (3 x 15 mL). The combined organic phases were washed with brine, dried, filtered through a short plug of silica gel and washed with 20 ml of the same solvent. Evaporation of the solvent gave 2.77 g of compound 27 as a pale viscous oil, very pure as confirmed by 1 H-NMR.
28的制备(见流程6)The preparation of 28 (see scheme 6)
向50ml烧瓶内装入氢化钠(60％油分散系，400mg，10mmol)，用己烷洗涤三次。加入DMF(15ml)，搅拌该悬液，同时历时15分钟加入化合物27(2.53g，5.19mmol)的5ml无水DMF溶液。将反应物搅拌15分钟，然后冷却至0℃以下，历时5分钟加入1-溴-2-甲基-2-丙烯(1ml，10mmol)，然后在室温下搅拌2小时。使混合物在己烷/冰冷的氯化铵溶液之间分配，如 27的制备所述进行操作，粗产物经过色谱纯化，得到2.20g无色的油，1H-NMR和元素分析证实是纯的。在氮下，在100ml Morton烧瓶内，将该物质(2.38g，4.4mmol)溶于50mlEtOAc。加入150mg 5％披钯碳，将混合物在1大气压氢下搅拌20分钟。过滤除去催化剂，蒸发溶剂，得到2.35g 28，为无色的油，1H-NMR证实是纯的。Sodium hydride (60% oil dispersion, 400 mg, 10 mmol) was charged into a 50 ml flask and washed three times with hexane. DMF (15 ml) was added and the suspension was stirred while a solution of compound 27 (2.53 g, 5.19 mmol) in 5 ml of anhydrous DMF was added over 15 minutes. The reaction was stirred for 15 minutes, then cooled to below 0 °C, 1-bromo-2-methyl-2-propene (1 ml, 10 mmol) was added over 5 minutes, then stirred at room temperature for 2 hours. The mixture was partitioned between hexane/ice-cold ammonium chloride solution and worked up as described for the preparation of 27. The crude product was purified by chromatography to give 2.20 g of a colorless oil, pure by 1 H-NMR and elemental analysis . This material (2.38 g, 4.4 mmol) was dissolved in 50 ml EtOAc in a 100 ml Morton flask under nitrogen. 150 mg of 5% palladium on carbon was added, and the mixture was stirred under 1 atmosphere of hydrogen for 20 minutes. The catalyst was removed by filtration and the solvent was evaporated to give 2.35 g of 28 as a colorless oil, pure by 1 H-NMR.
29的制备(见流程6)The preparation of 29 (see process 6)
向带有磁搅拌器的50ml烧瓶内装入醚28(2.0g，3.68mmol)的40ml CH2Cl2与2ml水溶液。将其在氮下搅拌，在＜10℃冰浴中冷却，同时一齐加入2，3-二氯-5，6-二氰基-1，4-苯醌(DDQ)(920mg，4.05mmol)。除去冰浴，将混合物在室温下搅拌1小时。用吸滤法过滤金黄色悬液，滤饼用2×10ml CH2Cl2洗涤，滤液用0.2N NaOH萃取(2×25ml)。将有机层干燥，浓缩，得到苍白色油，经过色谱纯化，得到1.53g无色的油，元素分析证实是纯的。将其溶于25ml CH2Cl2，在氮下、在冰浴中搅拌，同时先后加入DMAP(854mg，7mmol)、EDCI(1.34g，7mmol)和N-t-BOC-O-苄基-L-丝氨酸(2.07g，7mmol)。除去冷却浴，将混合物在室温下搅拌2小时。然后倒在迅速搅拌着的50ml冰冷的0.5N HCl与20ml CH2Cl2的混合物中，搅拌10分钟。分离各相，含水相用1×10ml CH2Cl2萃取；然后将合并后的有机相干燥，浓缩，得到苍白色油。经过色谱纯化，得到2.30g 29，为几乎无色的重油。TLC和1H-NMR显示是相当纯的。A 50 ml flask with a magnetic stirrer was charged with ether 28 (2.0 g, 3.68 mmol) in 40 ml CH2Cl2 and 2 ml aqueous solution. This was stirred under nitrogen and cooled in an <10°C ice bath while 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (920 mg, 4.05 mmol) was added all at once. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. The golden suspension was filtered by suction filtration, the filter cake was washed with 2×10 ml CH 2 Cl 2 , and the filtrate was extracted with 0.2N NaOH (2×25 ml). The organic layer was dried and concentrated to give a pale oil which was purified by chromatography to give 1.53 g of a colorless oil which was pure by elemental analysis. This was dissolved in 25ml CH2Cl2 and stirred in an ice bath under nitrogen while DMAP (854mg, 7mmol), EDCI (1.34g, 7mmol) and Nt-BOC-O-benzyl-L-serine were added successively (2.07g, 7mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. It was then poured into a rapidly stirred mixture of 50 mL of ice-cold 0.5N HCl and 20 mL of CH2Cl2 and stirred for 10 minutes. The phases were separated and the aqueous phase was extracted with 1 x 10 ml CH2Cl2 ; the combined organic phases were then dried and concentrated to give a pale oil. Purification by chromatography afforded 2.30 g of 29 as an almost colorless heavy oil. TLC and 1 H-NMR showed fairly pure.
30的制备(见流程6)The preparation of 30 (see process 6)
将甲硅烷基醚29溶于7ml无水吡啶，在冰浴中冷却。历时1分钟加入HF-吡啶配合物(4.5ml)，将溶液在室温下搅拌17小时，然后加热至50℃达4.5小时，转化停止。将混合物倒在冰水中，用3×50ml乙醚萃取。将合并后的有机相用水、1N HCl洗涤，然后干燥，浓缩，得到油。经过色谱纯化，得到1.23g所需的醇，为粘性油，以及365mg回收的29。将醇(1.14g，2.10mmol)溶于10ml DMF，加入重铬酸吡啶鎓(3.76g，10mmol)。21小时后，将混合物倒在冰水中，加入1N HCl，直至pH在3以下，然后加入固体亚硫酸氢钠，直至橙色消失。含水相用乙醚萃取(3×50ml)。将有机相合并，洗涤，干燥(Na2SO4)，浓缩。残余物经过硅胶色谱纯化，得到811mg粘性油，对继续反应来说是足够纯的。将酸溶于30ml EtOAc，加入200mg Pearlman催化剂。将浆液在50psi氢压下摇动4小时，加入300mg新鲜的催化剂，继续摇动2小时。然后过滤，蒸发溶剂，得到 30，为粘性胶，对进一步使用来说是足够纯的。The silyl ether 29 was dissolved in 7 ml of anhydrous pyridine and cooled in an ice bath. HF-pyridine complex (4.5ml) was added over 1 minute and the solution was stirred at room temperature for 17 hours, then heated to 50°C for 4.5 hours, at which point conversion ceased. The mixture was poured into ice water and extracted with 3 x 50ml ether. The combined organic phases were washed with water, 1N HCl, then dried and concentrated to an oil. Purification by chromatography afforded 1.23 g of the desired alcohol as a viscous oil and 365 mg of 29 recovered. Alcohol (1.14g, 2.10mmol) was dissolved in 10ml DMF, and pyridinium dichromate (3.76g, 10mmol) was added. After 21 h, the mixture was poured into ice water and 1 N HCl was added until the pH was below 3, then solid sodium bisulfite was added until the orange color disappeared. The aqueous phase was extracted with ether (3 x 50ml). The organic phases were combined, washed, dried ( Na2SO4 ) and concentrated. The residue was chromatographed on silica gel to give 811 mg of a viscous oil, pure enough to continue the reaction. The acid was dissolved in 30ml EtOAc and 200mg Pearlman's catalyst was added. The slurry was shaken under 50 psi hydrogen pressure for 4 hours, 300 mg of fresh catalyst was added, and shaking was continued for 2 hours. It was then filtered and the solvent was evaporated to give 30 as a viscous gum, pure enough for further use.
苏氨酸二噻烷33(见流程7)Threonine dithiane 33 (see scheme 7)
在室温下，将戊基二噻烷32(Hirai《杂环》1990，30(2，Spec.Issue)，1101)(200mg，0.97mmol)溶于10ml CH2Cl2。加入N-(Z)-O-叔丁基-(L)-苏氨酸(900mg，2.91mmol)，然后加入DMAP(36mg，0.29mmol)。向该混合物中滴加二环己基碳二亚胺(DCC)(1M CH2Cl2溶液，2.9ml，2.9mmol)，然后在室温下搅拌过夜。将反应物用50ml乙醚(Et2O)稀释，过滤，浓缩。所得残余物上小(4”)硅胶重力柱，用4∶1己烷/EtOAc洗脱。从硅胶柱收集的洗脱液进一步经过径向色谱纯化，用4∶1己烷/EtOAc作为洗脱液。蒸发产物部分，保持在高真空(45℃，0.1托)下至恒重，得到500mg几乎无色的重油，被鉴定为二噻烷33(TLC Rf＝0.32，1H-NMR)。Amyldithiane 32 (Hirai "Heterocycles" 1990, 30(2, Spec. Issue), 1101) (200 mg, 0.97 mmol) was dissolved in 10 ml CH 2 Cl 2 at room temperature. N-(Z)-O-tert-butyl-(L)-threonine (900 mg, 2.91 mmol) was added followed by DMAP (36 mg, 0.29 mmol). Dicyclohexylcarbodiimide (DCC) (1M CH2Cl2 solution, 2.9ml, 2.9mmol) was added dropwise to the mixture, followed by stirring at room temperature overnight. The reaction was diluted with 50 ml diethyl ether ( Et2O ), filtered and concentrated. The resulting residue was applied to a small (4") silica gel gravity column eluting with 4:1 hexanes/EtOAc. The eluate collected from the silica gel column was further purified by radial chromatography using 4:1 hexanes/EtOAc as eluent The product fraction was evaporated and kept under high vacuum (45 °C, 0.1 Torr) to constant weight to give 500 mg of almost colorless heavy oil identified as dithiane 33 (TLC Rf = 0.32, 1 H-NMR).
苏氨酸羧酸35(见流程7)Threonine carboxylic acid 35 (see scheme 7)
将苏氨酸二噻烷33(500mg，1.01mmol)在室温下溶于10ml 9∶1CH3CN/H2O混合物。加入[双(三氟乙酰氧基)碘]苯(650mg，1.50mmol)，将反应物搅拌10分钟。加入饱和NaHCO3(20ml)，溶液用Et2O萃取(3×20ml)。将醚层经MgSO4干燥，过滤，浓缩。醛34对直接用于下面的反应来说是足够纯的(TLC，GC/MS)。将粗的醛溶于15ml(4.95mmol)CrO3试剂(从1g CrO3、30ml CH3CO2H和1ml吡啶制备)，在室温下搅拌过夜。将溶液用30ml冷水稀释，用Et2O萃取(3×30ml)。将有机层用30ml盐水洗涤，经MgSO4干燥，过滤，浓缩。残余物经过径向色谱纯化，用含有2％CH3CO2H的2∶1庚烷/EtOAc作为洗脱剂。TLC和1H-NMR测定羧酸35(120mg)是相当纯的。Threonine dithiane 33 (500 mg, 1.01 mmol) was dissolved in 10 ml of a 9:1 CH 3 CN/H 2 O mixture at room temperature. [Bis(trifluoroacetoxy)iodo]benzene (650 mg, 1.50 mmol) was added and the reaction was stirred for 10 minutes. Sat NaHCO3 (20ml) was added and the solution was extracted with Et2O (3 x 20ml). The ether layer was dried over MgSO4 , filtered and concentrated. Aldehyde 34 was pure enough (TLC, GC/MS) to be used directly in the next reaction. The crude aldehyde was dissolved in 15 ml (4.95 mmol) CrO3 reagent (prepared from 1 g CrO3 , 30 ml CH3CO2H and 1 ml pyridine) and stirred overnight at room temperature. The solution was diluted with 30ml of cold water and extracted with Et2O (3 x 30ml). The organic layer was washed with 30 ml brine, dried over MgSO4 , filtered and concentrated. The residue was purified by radial chromatography using 2:1 heptane/EtOAc containing 2% CH3CO2H as eluent. Carboxylic acid 35 (120 mg) was fairly pure as determined by TLC and 1 H-NMR.
苏氨酸羟基羧酸36(见流程7)Threonine hydroxycarboxylic acid 36 (see scheme 7)
将苏氨酸羧酸35(137mg，0.324mmol)在3ml三氟乙酸中搅拌10分钟，将混合物在旋转蒸发器上浓缩。将残余物在高真空(0.05mm)下干燥过夜。羟基酸36(119mg)直接用于下面的步骤。Threonine carboxylic acid 35 (137mg, 0.324mmol) was stirred in 3ml of trifluoroacetic acid for 10 minutes and the mixture was concentrated on a rotary evaporator. The residue was dried overnight under high vacuum (0.05 mm). Hydroxy acid 36 (119 mg) was used directly in the next step.
N-Cbz-苏氨酸双内酯37(见流程7)N-Cbz-threonine dilactone 37 (see scheme 7)
将苏氨酸羟基羧酸36(119mg，0.324mmol)溶于1ml苯，加入AldrithiolTM-2(85mg，0.39mmol)，然后加入三苯膦(0.39mol，101mg)，将反应物搅拌过夜。粗的硫酯用15ml CH3CN稀释。在另一支带有回流冷凝器的烧瓶内装入1.2ml(1.16mmol)1.0M AgClO4的甲苯溶液，然后加入32ml CH3CN。将该溶液加热至回流速率为5-10滴每秒(油浴～160℃)。然后历时2小时将硫酯溶液经由加液漏斗滴加至冷凝器顶部。将混合物另外回流30分钟，冷却，浓缩。将残余物用10ml0.5M KCN稀释，用苯萃取(3×20ml)。将苯层合并，用20ml水洗涤，经MgSO4干燥，过滤，浓缩。然后将残余物溶于10ml 2∶1戊烷/Et2O，过滤。用2∶1戊烷/Et2O洗涤固体，将有机溶液合并，浓缩。径向色谱纯化(2∶1戊烷/Et2O作为洗脱剂)得到34mg双内酯37，TLC(Rf＝0.22)和1H-NMR证实是相当纯的。Threonine hydroxycarboxylic acid 36 (119 mg, 0.324 mmol) was dissolved in 1 ml of benzene, Aldrithiol ™ -2 (85 mg, 0.39 mmol) was added, followed by triphenylphosphine (0.39 mol, 101 mg), and the reaction was stirred overnight. The crude thioester was diluted with 15ml CH3CN . In another flask with a reflux condenser, 1.2ml (1.16mmol) of 1.0M AgClO 4 in toluene was charged, and then 32ml of CH 3 CN was added. The solution was heated to a reflux rate of 5-10 drops per second (oil bath ~160°C). The thioester solution was then added dropwise to the top of the condenser via the addition funnel over 2 hours. The mixture was refluxed for an additional 30 minutes, cooled and concentrated. The residue was diluted with 10ml 0.5M KCN and extracted with benzene (3 x 20ml). The benzene layers were combined, washed with 20 ml of water, dried over MgSO4 , filtered and concentrated. The residue was then dissolved in 10 ml 2:1 pentane/ Et2O and filtered. The solid was washed with 2:1 pentane/ Et2O and the organic solutions were combined and concentrated. Purification by radial chromatography (2:1 pentane/ Et2O as eluent) afforded 34 mg of dilactone 37, which was fairly pure by TLC ( Rf = 0.22) and1H -NMR.
3-氨基-4，7，9-三甲基双内酯38(见流程7)3-amino-4,7,9-trimethylbis-lactone 38 (see scheme 7)
在用氮净化的500ml Parr瓶内，将N-Cbz-苏氨酸双内酯37(34mg，0.097mmol)溶于10ml甲醇。向该溶液中加入10mg Pd(黑)，将混合物在45psi氢压下摇动1小时。过滤催化剂，蒸发溶剂，得到游离的胺38(20mg，100％)。该胺是足够纯的(1H-NMR)，无需进一步纯化即可使用。In a nitrogen purged 500 ml Parr bottle, N-Cbz-threonine dilactone 37 (34 mg, 0.097 mmol) was dissolved in 10 ml methanol. To this solution was added 10 mg of Pd (black) and the mixture was shaken under 45 psi hydrogen pressure for 1 hour. The catalyst was filtered and the solvent was evaporated to give the free amine 38 (20 mg, 100%). The amine was sufficiently pure ( 1H -NMR) to be used without further purification.
3-苄基-4-羟基-5-甲基丁内酯40(见流程8)3-benzyl-4-hydroxy-5-methylbutyrolactone 40 (see scheme 8)
在用氮净化的500ml Parr瓶内，将戊酸39(Shimano等《四面体快报》1998，39，4363)(1.8g，5.23mmol)溶于30ml甲醇。向该溶液中加入150mg 10％披钯碳，然后加入6滴浓HCl。将混合物在50psi氢压下摇动3小时。通过硅藻土过滤催化剂，浓缩溶液。将残余物溶于30ml CH2Cl2，用水洗涤(1×10ml)。将溶液经MgSO4干燥，过滤，浓缩。粗的1H-NMR和GC/MS揭示预期的丁内酯40与4-甲基茴香醚的比例为4∶1(v/v)。该物质(GC测定纯度为60％)直接用于下面的反应。Valeric acid 39 (Shimano et al. Tetrahedron Letters 1998, 39, 4363) (1.8 g, 5.23 mmol) was dissolved in 30 ml methanol in a 500 ml Parr bottle purged with nitrogen. To this solution was added 150 mg of 10% palladium on carbon followed by 6 drops of concentrated HCl. The mixture was shaken under 50 psi hydrogen pressure for 3 hours. The catalyst was filtered through celite and the solution was concentrated. The residue was dissolved in 30ml CH2Cl2 and washed with water (1 x 10ml). The solution was dried over MgSO4 , filtered and concentrated. Crude1H -NMR and GC/MS revealed the expected ratio of butyrolactone 40 to 4-methylanisole of 4:1 (v/v). This material (60% pure by GC) was used directly in the next reaction.
3-苄基-5-甲基丁烯羟酸内酯41(见流程8)3-Benzyl-5-methylbutenolide 41 (see scheme 8)
将3-苄基-4-羟基-5-甲基丁内酯40(60％纯度，1.7g，8.25mmol)溶于25ml CH2Cl2，冷却至0℃。搅拌该溶液，同时先后加入三乙胺(2.3ml，16.5mmol)、DMAP(500mg，4.13mmol)和对-甲苯磺酰氯(9.0mmol，1.7g)。使反应物温热至室温，搅拌30小时。反应物用50mlEt2O稀释，用5％ NaHCO3(25ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。残余物经由径向色谱纯化，用2∶1戊烷/Et2O作为洗脱剂，得到677mg丁烯羟酸内酯41(GC和1H-NMR测定纯度＞95％)。3-Benzyl-4-hydroxy-5-methylbutyrolactone 40 (60% purity, 1.7 g, 8.25 mmol) was dissolved in 25 ml CH2Cl2 and cooled to 0°C. The solution was stirred while triethylamine (2.3ml, 16.5mmol), DMAP (500mg, 4.13mmol) and p-toluenesulfonyl chloride (9.0mmol, 1.7g) were added sequentially. The reaction was allowed to warm to room temperature and stirred for 30 hours. The reaction was diluted with 50ml Et2O and washed with 5% NaHCO3 (25ml). The solution was dried over MgSO4 , filtered and concentrated. The residue was purified via radial chromatography using 2:1 pentane/ Et2O as eluent to afford 677 mg of butenolide 41 (>95% pure by GC and1H -NMR).
顺式-3-苄基-5-甲基丁内酯42(见流程8)Cis-3-benzyl-5-methylbutyrolactone 42 (see scheme 8)
在用氮净化的500ml Parr瓶内，将3-苄基-5-甲基丁烯羟酸内酯41(677mg，3.60mmol)溶于30ml EtOAc。向该溶液中加入300mg 10％Pd/C，将混合物在45psi氢压下摇动过夜。过滤催化剂，蒸发溶剂。残余物经由径向色谱纯化，用2∶1戊烷/Et2O作为洗脱剂，得到484mg无色的油(1H-NMR(CDCl3)和GC测定纯物质收率71％)。3-Benzyl-5-methylbutenolide 41 (677mg, 3.60mmol) was dissolved in 30ml EtOAc in a nitrogen purged 500ml Parr bottle. To this solution was added 300 mg of 10% Pd/C and the mixture was shaken under 45 psi hydrogen pressure overnight. The catalyst was filtered and the solvent was evaporated. The residue was purified via radial chromatography using 2:1 pentane/ Et2O as eluent to afford 484 mg of a colorless oil ( 1H -NMR ( CDCl3 ) and GC yield 71% pure material).
2-苄基戊基二噻烷43(见流程8)2-Benzylpentyldithiane 43 (see scheme 8)
将顺式-3-苄基-5-甲基丁内酯42(550mg，2.89mmol)溶于15mlEt2O，冷却至-78℃。滴加氢化二异丁基铝(1.0M己烷溶液，3.47mmol，3.5ml)，将溶液在-78℃下搅拌2小时。历时15分钟加入甲醇(3.3ml)，将反应物在-78℃下搅拌另外30分钟。加入酒石酸钾钠(1.65g，5ml水溶液)，使反应物温热至室温，搅拌过夜。分离各层，含水层用Et2O萃取(2×10ml)。合并后的醚层用饱和NaHCO3和盐水洗涤(1×10ml)。将溶液经MgSO4干燥，过滤，浓缩。将粗的内半缩醛(555mg)溶于5mlCH2Cl2，冷却至0℃。加入1，3-丙二硫醇(3.46mmol，0.35ml)，然后加入0.37ml(2.89mmol)三氟化硼醚合物。使反应物温热至室温，搅拌过夜。加入饱和NaHCO3(20ml)，将混合物搅拌1小时。分离各层，含水层用CH2Cl2萃取(2×10ml)。将合并后的有机层用盐水洗涤(1×20ml)，经MgSO4干燥，过滤，浓缩。残余物经由径向色谱纯化，用3∶l己烷/EtOAc作为洗脱剂，得到560mg黄色的油(1H-NMR和GC测定纯物质收率69％)，被鉴定为二噻烷43。Cis-3-benzyl-5-methylbutyrolactone 42 (550 mg, 2.89 mmol) was dissolved in 15 ml Et 2 O and cooled to -78°C. Diisobutylaluminum hydride (1.0M hexane solution, 3.47mmol, 3.5ml) was added dropwise, and the solution was stirred at -78°C for 2 hours. Methanol (3.3ml) was added over 15 minutes and the reaction was stirred at -78°C for a further 30 minutes. Potassium sodium tartrate (1.65 g, 5 mL in water) was added and the reaction allowed to warm to room temperature and stir overnight. The layers were separated and the aqueous layer was extracted with Et2O (2 x 10ml). The combined ether layers were washed with saturated NaHCO 3 and brine (1×10 ml). The solution was dried over MgSO4 , filtered and concentrated. The crude lactol (555mg) was dissolved in 5ml CH2Cl2 and cooled to 0°C. 1,3-Propanedithiol (3.46mmol, 0.35ml) was added, followed by 0.37ml (2.89mmol) of boron trifluoride etherate. The reaction was allowed to warm to room temperature and stirred overnight. Sat NaHCO3 (20ml) was added and the mixture was stirred for 1 hour. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 10ml). The combined organic layers were washed with brine (1 x 20ml), dried over MgSO4 , filtered and concentrated. The residue was purified via radial chromatography using 3:1 hexane/EtOAc as eluent to afford 560 mg of a yellow oil (69% yield of pure material by 1 H-NMR and GC), identified as dithiane 43.
丝氨酸二噻烷44(见流程8)Serine dithiane 44 (see scheme 8)
将2-苄基戊基二噻烷43(560mg，1.99mmol)溶于5ml DMF，冷却至0℃。加入DMAP(0.29mmol，36mg)，然后加入EDCI(0.57g，2.98mmol)。然后加入N-t-BOC-O-苄基-(L)-丝氨酸(760mg，2.58mmol)，然后温热至室温，在室温下搅拌过夜。将反应物倒在迅速搅拌着的10ml冰冷的0.5N HCl与20ml 20％乙醚/己烷的混合物中，搅拌10分钟。分离各层，含水层用20％乙醚/己烷萃取(1×10ml)。将合并后的有机层用0.5N HCl(20ml)和盐水(2×20ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。将所得残余物保持在高真空(45℃，0.1托)下至恒重，得到1.06g几乎无色的重油，被鉴定为二噻烷44(TLCRf＝0.3，3∶1己烷/EtOAc)。2-Benzylpentyldithiane 43 (560mg, 1.99mmol) was dissolved in 5ml DMF and cooled to 0°C. DMAP (0.29mmol, 36mg) was added followed by EDCI (0.57g, 2.98mmol). Then Nt-BOC-O-benzyl-(L)-serine (760 mg, 2.58 mmol) was added, followed by warming to room temperature and stirring at room temperature overnight. The reaction was poured into a rapidly stirred mixture of 10 mL of ice-cold 0.5N HCl and 20 mL of 20% ether/hexane and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with 20% ether/hexane (1 x 10 mL). The combined organic layers were washed with 0.5N HCl (20ml) and brine (2x20ml). The solution was dried over MgSO4 , filtered and concentrated. The resulting residue was kept under high vacuum (45 °C, 0.1 Torr) to constant weight to afford 1.06 g of a nearly colorless heavy oil identified as dithiane 44 (TLCR f = 0.3, 3:1 hexane/EtOAc) .
N-t-BOC-O-苄基丝氨酸羧酸45(见流程8)N-t-BOC-O-benzylserine carboxylic acid 45 (see scheme 8)
在室温下将丝氨酸二噻烷44(1.06g，1.90mmol)溶于20ml 9∶1CH2CN/H2O混合物。加入[双(三氟乙酰氧基)碘]苯(1.2g，2.82mmol)，将反应物搅拌10分钟。加入饱和NaHCO3(40ml)，溶液用Et2O萃取(3×40ml)。将醚层经MgSO4干燥，过滤，浓缩。醛对直接用于下面的反应来说是足够纯的(TLC，GC/MS，1H-NMR)。将粗的醛溶于30ml(9.70mmol)CrO3试剂(从1g CrO3、30ml CH3CO2H和1ml吡啶制备)，在室温下搅拌过夜。将溶液用60ml冷水稀释，用Et2O萃取(3×60ml)。将有机层用2×60ml盐水洗涤，经MgSO4干燥，过滤，浓缩。将残余物溶于100ml 2∶1庚烷/EtOAc，蒸发。残余物经由径向色谱纯化，用含有2％CH3CO2H的1.5∶1庚烷/EtOAc作为洗脱剂。TLC和1H-NMR测定羧酸(536mg)是相当纯的，在CDCl3中有两种明显的t-BOC旋转异构体，但在丙酮-d6中没有。Serine dithiane 44 (1.06 g, 1.90 mmol) was dissolved in 20 ml of a 9: 1 CH2CN/ H2O mixture at room temperature. [Bis(trifluoroacetoxy)iodo]benzene (1.2 g, 2.82 mmol) was added and the reaction was stirred for 10 minutes. Sat NaHCO3 (40ml) was added and the solution was extracted with Et2O (3x40ml). The ether layer was dried over MgSO4 , filtered and concentrated. The aldehyde was sufficiently pure (TLC, GC/MS, 1 H-NMR) to be used directly in the following reaction. The crude aldehyde was dissolved in 30 ml (9.70 mmol) CrO3 reagent (prepared from 1 g CrO3 , 30 ml CH3CO2H and 1 ml pyridine) and stirred overnight at room temperature. The solution was diluted with 60ml of cold water and extracted with Et2O (3 x 60ml). The organic layer was washed with 2 x 60 ml brine, dried over MgSO4 , filtered and concentrated. The residue was dissolved in 100 ml 2:1 heptane/EtOAc and evaporated. The residue was purified via radial chromatography using 1.5:1 heptane/EtOAc containing 2% CH3CO2H as eluent. The carboxylic acid (536 mg) was fairly pure by TLC and 1 H-NMR, with two distinct t-BOC rotamers in CDCl 3 but not in acetone-d 6 .
N-t-BOC-丝氨酸双内酯47(见流程8)N-t-BOC-serine dilactone 47 (see scheme 8)
在用氮净化的500ml Parr瓶内，将N-t-BOC-O-苄基丝氨酸羧酸45(536mg，1.11mmol)溶于15ml EtOAc。向该溶液中加入390mg 10％Pd/C，将混合物在50psi氢压下摇动17小时。通过硅藻土过滤催化剂，蒸发溶剂，得到羟基酸46(440mg)。将粗的羟基酸46溶于23ml苯，在室温下加入三苯膦(0.34g，1.28mmol)。滴加二异丙基偶氮二羧酸酯(DIAD，0.25ml，1.28mmol)，将反应物在室温下搅拌过夜。浓缩溶液，所得残余物上小(4”)重力柱，用2∶1己烷/EtOAc洗脱。硅胶柱洗脱液进一步经过径向色谱纯化，用2∶1戊烷/乙醚作为洗脱液。蒸发产物部分，得到132mg黄色的油，被鉴定为N-t-BOC-丝氨酸双内酯47(TLC Rf＝0.32，1H-NMR证实是相当纯的)。In a nitrogen purged 500ml Parr bottle, Nt-BOC-O-benzylserinecarboxylic acid 45 (536mg, 1.11mmol) was dissolved in 15ml EtOAc. To this solution was added 390 mg of 10% Pd/C and the mixture was shaken under 50 psi hydrogen pressure for 17 hours. The catalyst was filtered through celite and the solvent was evaporated to give hydroxyacid 46 (440 mg). The crude hydroxy acid 46 was dissolved in 23ml benzene and triphenylphosphine (0.34g, 1.28mmol) was added at room temperature. Diisopropylazodicarboxylate (DIAD, 0.25ml, 1.28mmol) was added dropwise and the reaction was stirred at room temperature overnight. The solution was concentrated and the resulting residue was applied to a small (4") gravity column eluting with 2:1 hexane/EtOAc. The silica column eluate was further purified by radial chromatography using 2:1 pentane/ether as eluent Evaporation of the product fraction gave 132 mg of a yellow oil identified as Nt-BOC-serine dilactone 47 (TLC Rf = 0.32, fairly pure by 1 H-NMR).
3-氨基-7-苄基-9-甲基双内酯48(见流程8)3-amino-7-benzyl-9-methyldilactone 48 (see scheme 8)
将N-t-BOC-丝氨酸双内酯47(132mg，0.35mmol)在3ml三氟乙酸中搅拌30分钟，在旋转蒸发器上浓缩反应物。将残余物在高真空(0.05mm)下干燥过夜。1H-NMR测定胺48(0.35mmol)的三氟乙酸盐是相当纯的，无需进一步纯化即可使用。Nt-BOC-serine dilactone 47 (132mg, 0.35mmol) was stirred in 3ml of trifluoroacetic acid for 30 minutes and the reaction was concentrated on a rotary evaporator. The residue was dried overnight under high vacuum (0.05mm). The trifluoroacetate salt of amine 48 (0.35 mmol) was determined to be fairly pure by 1 H-NMR and used without further purification.
3-(3-氯苯氧基)苯胺
向搅拌着的叔丁醇钾(12.3g)的DMSO(100ml)溶液中一齐加入3-氯苯酚(12.86g)。将所得溶液在室温下搅拌5分钟，然后一齐加入3-氟硝基苯(12.70g)。将所得深色混合物在120℃下加热12小时，冷却至室温，然后倒在水(700ml)中。所得混合物用乙醚萃取(2×200ml)。将有机部分用2N NaOH(100ml)洗涤，然后用水(100ml)洗涤。干燥(MgSO4)后，蒸发溶剂，蒸馏所得深色的油，得到3-(3-氯苯氧基)硝基苯，为黄色的油，在0.05mm下的b.p.135-140℃。To a stirred solution of potassium tert-butoxide (12.3g) in DMSO (100ml) was added 3-chlorophenol (12.86g) all at once. The resulting solution was stirred at room temperature for 5 minutes, then 3-fluoronitrobenzene (12.70 g) was added all at once. The resulting dark mixture was heated at 120°C for 12 hours, cooled to room temperature and poured into water (700ml). The resulting mixture was extracted with ether (2 x 200ml). The organic portion was washed with 2N NaOH (100ml) and then with water (100ml). After drying ( MgSO4 ), the solvent was evaporated and the resulting dark oil was distilled to give 3-(3-chlorophenoxy)nitrobenzene as a yellow oil, bp 135-140 °C at 0.05 mm.
在Parr摇动器上，使3-(3-氯苯氧基)硝基苯(14g)与5％硫化披钯碳(1.25g)在EtOAc(150ml)中的混合物受到氢气氛(最初压力＝50psi)处理。4小时后，将混合物充分脱气(用氮代替氢)，干燥(MgSO4)，过滤(#50 Whatman纸)。蒸发溶剂，得到淡黄色油(12g)，GC测定纯度＞96％。1H-NMR(CDCl3)和GC/MS(m/e＝219，221)与3-(3-氯苯氧基)苯胺是一致的。A mixture of 3-(3-chlorophenoxy)nitrobenzene (14 g) and 5% palladium sulfide on carbon (1.25 g) in EtOAc (150 ml) was subjected to an atmosphere of hydrogen on a Parr shaker (initial pressure = 50 psi )deal with. After 4 hours, the mixture was degassed well (nitrogen instead of hydrogen), dried ( MgSO4 ), filtered (#50 Whatman paper). Evaporation of the solvent gave a light yellow oil (12 g) >96% pure by GC. 1 H-NMR (CDCl 3 ) and GC/MS (m/e = 219, 221) were consistent with 3-(3-chlorophenoxy)aniline.
3-(4-三氟甲基苯氧基)苯胺
向搅拌着的3-羟基苯胺(6.55g)与4-氟三氟甲苯(9.85g)的DMSO(50m l)溶液中一齐加入叔丁醇钾(7.86g)。将所得深色溶液在95℃下加热4小时，冷却至室温，然后倒在水(600ml)中。混合物用乙醚萃取(3×125ml)。将有机相用2N氢氧化钠(2×75ml)和水(100ml)洗涤，干燥(MgSO4)，蒸发溶剂，得到深色的油。蒸馏该油，得到标题苯胺，为无色的油(8.7g)，在0.15mm下的b.p.110-112℃。To a stirred solution of 3-hydroxyaniline (6.55g) and 4-fluorobenzotrifluoride (9.85g) in DMSO (50ml) was added potassium tert-butoxide (7.86g) all at once. The resulting dark solution was heated at 95°C for 4 hours, cooled to room temperature and poured into water (600ml). The mixture was extracted with ether (3 x 125ml). The organic phase was washed with 2N sodium hydroxide (2 x 75ml) and water (100ml), dried ( MgSO4 ) and the solvent evaporated to give a dark oil. Distillation of the oil gave the title aniline as a colorless oil (8.7g), bp 110-112°C at 0.15mm.
4-(4-三氟甲基苯硫基)苯胺
向在冰浴中冷却的搅拌着的4-氟三氟甲苯(9.85g)与4-氨基苯硫酚(7.51g)的DMSO(60ml)溶液中一齐加入叔丁醇钾(6.73g)。将所得混合物在0℃下搅拌10分钟，然后在60℃下搅拌过夜。冷却后，将混合物倒在水(600ml)中，所得混合物用乙醚萃取(2×200ml)。将有机相用2N氢氧化钠(50ml)洗涤，然后用水(50ml)洗涤。干燥(MgSO4)后，蒸发溶剂，得到褐色固体。从己烷中重结晶，得到标题苯胺，为黄色固体，m.p.97-99℃。To a stirred solution of 4-fluorobenzotrifluoride (9.85g) and 4-aminothiophenol (7.51g) in DMSO (60ml) cooled in an ice bath was added potassium tert-butoxide (6.73g) all at once. The resulting mixture was stirred at 0°C for 10 minutes and then at 60°C overnight. After cooling, the mixture was poured into water (600ml) and the resulting mixture was extracted with ether (2 x 200ml). The organic phase was washed with 2N sodium hydroxide (50ml) and then with water (50ml). After drying ( MgSO4 ), the solvent was evaporated to give a tan solid. Recrystallization from hexanes gave the title aniline as a yellow solid, mp 97-99°C.
4-(3-三氟甲基苄基)苯胺
向搅拌着的镁屑(1.09g)在无水THF(10ml)中的混合物中加入4-溴-N，N-双(三甲基甲硅烷基)苯胺(9.48g)的无水THF(75ml)溶液，制得格利雅试剂。向无水THF(25ml)中加入CuCl2(0.20g)和LiCl(0.13g)并搅拌直至形成均匀溶液，制得第二种催化剂Li2CuCl4(0.33g)的溶液。然后向3-三氟甲基苄基溴(7.17g)的无水THF(75ml)溶液中加入这种催化剂溶液。将橙红色溶液在冰浴(N2气氛)中冷却，向其中经由套管迅速转移上述格利雅溶液(预先在冰浴中冷却)。在0℃下搅拌15分钟后，将混合物在室温下搅拌过夜。加入饱和NH4Cl溶液(25ml)猝灭反应混合物。分离有机相，干燥(MgSO4)，蒸发溶剂，得到深色的油(11g)。向该油中加入4N HCl(50ml)，将所得混合物在室温下搅拌3小时。向混合物中小心地加入固体碳酸钠至碱性，然后用乙醚萃取(3×100ml)。将有机相干燥(MgSO4)，蒸发溶剂。加入EtOAc(100ml)，滗析溶液除去一些不溶性物质。再次蒸发溶剂，用色谱(硅胶，3∶1己烷/EtOAc)纯化残余物。收集第二份洗脱液，得到橙色的油，颜色迅速变深。NMR(CDCl3)和GC/MS(m/e＝251)与标题化合物是一致的。该物质转化为HCl盐，得到褐色固体。To a stirred mixture of magnesium turnings (1.09g) in anhydrous THF (10ml) was added 4-bromo-N,N-bis(trimethylsilyl)aniline (9.48g) in anhydrous THF (75ml ) solution to obtain the Grignard reagent. A solution of the second catalyst Li2CuCl4 ( 0.33g ) was prepared by adding CuCl2 (0.20g) and LiCl (0.13g) to anhydrous THF (25ml) and stirring until a homogeneous solution formed. This catalyst solution was then added to a solution of 3-trifluoromethylbenzyl bromide (7.17g) in anhydrous THF (75ml). The orange-red solution was cooled in an ice bath ( N2 atmosphere), into which the above Grignard solution (previously cooled in an ice bath) was quickly transferred via cannula. After stirring at 0°C for 15 minutes, the mixture was stirred at room temperature overnight. The reaction mixture was quenched by adding saturated NH4Cl solution (25ml). The organic phase was separated, dried ( MgSO4 ) and the solvent evaporated to give a dark oil (11 g). To the oil was added 4N HCl (50 ml), and the resulting mixture was stirred at room temperature for 3 hours. To the mixture was carefully added solid sodium carbonate to make basic, then extracted with ether (3 x 100ml). The organic phase was dried ( MgSO4 ) and the solvent was evaporated. EtOAc (100ml) was added and the solution was decanted to remove some insoluble material. The solvent was evaporated again and the residue was purified by chromatography (silica gel, 3:1 hexane/EtOAc). The second eluate was collected to give an orange oil which rapidly darkened. NMR ( CDCl3 ) and GC/MS (m/e=251) were consistent with the title compound. This material was converted to the HCl salt to give a tan solid.
4-(3-三氟甲基苯甲酰基)苯胺
将搅拌着的4-溴-N，N-双(三甲基甲硅烷基)苯胺(9.24g)的无水THF(100ml)溶液在氩气氛下冷却至-78℃。向其中缓慢加入2.5M正丁基锂的己烷溶液(12ml)。加入完全后，将反应混合物在-78℃下搅拌10分钟，然后滴加N-甲基-N-甲氧基-3-三氟甲基苯甲酰胺(6.8g)的无水THF(25ml)溶液。加入完全后，将混合物在-78℃下搅拌1小时，然后除去冷却浴，使反应温度升至10℃。加入饱和NH4Cl溶液(50ml)，再加入水(10ml)，猝灭反应。分离有机相，干燥(MgSO4)，蒸发溶剂，得到黄色液体(12g)。将其溶于乙醚(100ml)，加入4N HCl(100ml)。将所得混合物在室温下搅拌30分钟，在此期间分离固体。过滤该固体，用若干批乙醚洗涤，然后小心地加入到搅拌着的饱和NaHCO3溶液(100ml)中。所得混合物用乙醚萃取(2×100ml)，将有机相干燥(MgSO4)，蒸发溶剂，得到黄白色固体(5.7g)。从甲醇/水中重结晶，得到白色固体，m.p.130-131℃。光谱数据与标题化合物是一致的。A stirred solution of 4-bromo-N,N-bis(trimethylsilyl)aniline (9.24g) in anhydrous THF (100ml) was cooled to -78°C under an argon atmosphere. A 2.5M hexane solution (12 ml) of n-butyllithium was slowly added thereto. After complete addition, the reaction mixture was stirred at -78°C for 10 minutes, then N-methyl-N-methoxy-3-trifluoromethylbenzamide (6.8 g) in anhydrous THF (25 ml) was added dropwise solution. After the addition was complete, the mixture was stirred at -78°C for 1 hour, then the cooling bath was removed and the reaction temperature was allowed to rise to 10°C. The reaction was quenched by the addition of saturated NH4Cl solution (50ml) followed by water (10ml). The organic phase was separated, dried ( MgSO4 ) and the solvent was evaporated to give a yellow liquid (12g). This was dissolved in diethyl ether (100ml) and 4N HCl (100ml) was added. The resulting mixture was stirred at room temperature for 30 minutes, during which time a solid separated. The solid was filtered, washed with several portions of diethyl ether, then carefully added to a stirred saturated NaHCO3 solution (100ml). The resulting mixture was extracted with diethyl ether (2 x 100ml), the organic phase was dried ( MgSO4 ) and the solvent was evaporated to give an off-white solid (5.7g). Recrystallization from methanol/water gave a white solid, mp 130-131°C. Spectral data were consistent with the title compound.
2-氨基-5-(4-三氟甲基苯氧基)苯甲酸乙酯 Ethyl 2-amino-5-(4-trifluoromethylphenoxy)benzoate
向机械搅拌着的叔丁醇钾(15.71g)的DMSO(75ml)溶液中一齐加入5-羟基邻氨基苯甲酸(10.2g)。将混合物在氩气氛和室温下搅拌10分钟，然后加入4-氟三氟甲苯(11.16g)，将所得混合物在75-80℃下搅拌加热过夜。冷却后，将混合物倒在水(600ml)中，将pH调至大约2.5。过滤所得固体，用若干批水洗涤，然后从甲醇/水(木炭)中重结晶，得到黄褐色固体(13.5g)，m.p.165-167℃。将该固体溶于无水乙醇(250ml)，小心地加入浓硫酸(15ml)。将所得混合物在回流下加热24小时，然后蒸发大部分乙醇。将残余物小心地加入到冰水(600ml)中，向混合物中缓慢加入50％NaOH溶液至碱性，然后用乙醚萃取(2×150ml)。有机相用水(100ml)洗涤，然后用饱和NaCl溶液(50ml)洗涤。干燥(MgSO4)后，蒸发溶剂，得到黄色的油，GC纯度约98％。GC/MS显示母体离子m/e＝325，与标题化合物是一致的。To a mechanically stirred solution of potassium tert-butoxide (15.71 g) in DMSO (75 mL) was added all at once 5-hydroxyanthranilic acid (10.2 g). The mixture was stirred at room temperature under an argon atmosphere for 10 minutes, then 4-fluorobenzotrifluoride (11.16 g) was added, and the resulting mixture was stirred and heated at 75-80° C. overnight. After cooling, the mixture was poured into water (600ml) and the pH was adjusted to about 2.5. The resulting solid was filtered, washed with several batches of water and then recrystallized from methanol/water (charcoal) to give a tan solid (13.5g), mp 165-167°C. This solid was dissolved in absolute ethanol (250ml) and concentrated sulfuric acid (15ml) was carefully added. The resulting mixture was heated at reflux for 24 hours, then most of the ethanol was evaporated. The residue was carefully added to ice water (600ml), and 50% NaOH solution was slowly added to the mixture to make basic, then extracted with diethyl ether (2 x 150ml). The organic phase was washed with water (100ml) and then with saturated NaCl solution (50ml). After drying ( MgSO4 ), the solvent was evaporated to give a yellow oil with a GC purity of about 98%. GC/MS showed the parent ion m/e = 325, consistent with the title compound.
2-氨基苯并降冰片烷 2-Aminobenzonorbornane
向在氩气氛下冷却至0℃的搅拌着的苯并降冰片烯(2.84g)的无水THF(8ml)溶液中迅速加入1M硼烷的THF溶液(6.7ml)。将溶液在0℃下搅拌10分钟，然后在室温下搅拌90分钟。再次将反应混合物冷却至0℃，一齐加入羟胺-O-磺酸(1.58g)。除去冰浴，将反应混合物在室温下搅拌2小时。加入1N HCl(25ml)和乙醚(20ml)，继续搅拌10分钟。分离各相，弃去有机相。向含水相中小心地加入50％NaOH溶液至碱性，然后用乙醚萃取(3×30ml)。将有机相干燥(MgSO4)，蒸发溶剂，得到黄色液体(1.35g)，GC判断其纯度为98％。NMR(CDCl3)和GC/MS(m/e＝159)与标题化合物是一致的。To a stirred solution of benzonorbornene (2.84g) in anhydrous THF (8ml) cooled to 0°C under argon atmosphere was added 1M borane in THF (6.7ml) rapidly. The solution was stirred at 0°C for 10 minutes, then at room temperature for 90 minutes. The reaction mixture was cooled to 0°C again, and hydroxylamine-O-sulfonic acid (1.58 g) was added all at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. 1N HCl (25ml) and diethyl ether (20ml) were added and stirring was continued for 10 minutes. The phases were separated and the organic phase was discarded. 50% NaOH solution was carefully added to the aqueous phase to make basic, then extracted with diethyl ether (3 x 30ml). The organic phase was dried ( MgSO4 ) and the solvent was evaporated to give a yellow liquid (1.35g) 98% pure by GC. NMR ( CDCl3 ) and GC/MS (m/e = 159) were consistent with the title compound.
流程9 Process 9
(3-三氟甲基苄氧基甲基)降冰片基胺53混合物的制备Preparation of (3-trifluoromethylbenzyloxymethyl)norbornylamine 53 mixture
该混合物的制备如流程9所述。因而，将外-与内-降冰片烯羧酸49(～1∶4)(7.0g)、2-碘丙烷(12.8g)与碳酸钾(10.4g)在DMSO(40ml)中的混合物在55℃下搅拌加热过夜。冷却后，将混合物用水(125ml)稀释，然后用戊烷萃取。将有机相干燥(MgSO4)，蒸发溶剂，得到无色的油(8.2g)。将该油加入到2-丙醇钠(3.6g)的2-丙醇(100ml)溶液中，将所得混合物在回流下加热16小时。除去2-丙醇，用水(200ml)稀释，用戊烷萃取，得到降冰片烯异丙酯50，为外向与内向异构体的52∶48混合物。将其经由色谱(硅胶，95∶5己烷/EtOAc)分离为纯的异构体。将 50-的外异构体(4.0g)溶于乙醚(50ml)，冷却至0℃，缓慢加入1M氢化锂铝的乙醚溶液(14ml)。加入完全后，将混合物在回流下加热1小时。冷却后，先后加入水(0.53ml)、15％NaOH溶液(0.53ml)和水(1.59ml)猝灭反应。将所得混合物干燥(MgSO4)，过滤，蒸发溶剂，得到外-醇 51(2.7g)，为无色液体。GC/MS(m/e＝124)与指定的结构是一致的。This mixture was prepared as described in Scheme 9. Thus, a mixture of exo- and endo-norbornene carboxylic acid 49 (~1:4) (7.0 g), 2-iodopropane (12.8 g) and potassium carbonate (10.4 g) in DMSO (40 ml) was prepared at 55 It was stirred and heated at ℃ overnight. After cooling, the mixture was diluted with water (125ml) and extracted with pentane. The organic phase was dried ( MgSO4 ) and the solvent was evaporated to give a colorless oil (8.2g). This oil was added to a solution of sodium 2-propoxide (3.6g) in 2-propanol (100ml) and the resulting mixture was heated at reflux for 16 hours. Removal of 2-propanol, dilution with water (200 mL) and extraction with pentane gave norbornene isopropyl ester 50 as a 52:48 mixture of exo and endo isomers. These were separated into the pure isomers via chromatography (silica gel, 95:5 hexane/EtOAc). The 50 -exoisomer (4.0g) was dissolved in ether (50ml), cooled to 0°C, and a 1M ether solution of lithium aluminum hydride (14ml) was slowly added. After the addition was complete, the mixture was heated at reflux for 1 hour. After cooling, the reaction was quenched by sequentially adding water (0.53ml), 15% NaOH solution (0.53ml) and water (1.59ml). The resulting mixture was dried ( MgSO4 ), filtered and the solvent was evaporated to give exo-alcohol 51 (2.7g) as a colorless liquid. GC/MS (m/e=124) was consistent with the assigned structure.
向搅拌着的氢化钾(1.0g)的无水THF(25ml)溶液中小心地加入51(2.7g)的THF(10ml)溶液。加入完全后，将混合物在室温下搅拌30分钟，然后一齐加入3-三氟甲基苄基溴(5.98g)(放热反应)。将反应物在回流下加热2小时，冷却，然后倒在水(150ml)中。用乙醚萃取(2×75ml)，干燥(MgSO4)，蒸发溶剂，得到黄色的油，经由色谱纯化(硅胶，97∶3己烷/丙酮)，得到纯的 52，为无色的油(5.2g)。NMR(CDCl3)和GC/MS(m/e＝282)与 52的结构是一致的。To a stirred solution of potassium hydride (1.0 g) in anhydrous THF (25 mL) was carefully added a solution of 51 (2.7 g) in THF (10 mL). After the addition was complete, the mixture was stirred at room temperature for 30 minutes, then 3-trifluoromethylbenzyl bromide (5.98 g) was added all at once (exothermic reaction). The reaction was heated at reflux for 2 hours, cooled and poured into water (150ml). Extraction with ether (2 x 75ml), drying ( MgSO4 ) and evaporation of the solvent gave a yellow oil which was purified by chromatography (silica gel, 97:3 hexane/acetone) to give pure 52 as a colorless oil (5.2 g). NMR ( CDCl3 ) and GC/MS (m/e=282) were consistent with the structure of 52 .
如前文所述经由硼烷/羟胺-O-磺酸操作实现 52向胺 53的非对映体混合物的转化(收率20％)。Conversion of 52 to the diastereomeric mixture of amine 53 was achieved via the borane/hydroxylamine-O-sulfonic acid procedure as described previously (yield 20%).
3-(3-吡啶基)-1-丙胺 3-(3-pyridyl)-1-propanamine
该胺是这样获得的，先按照B.Jursic等《合成》1988，(11)，868的操作将3-(3-吡啶基)-1-丙醇转化为相应的氯化物，再经由D.J.Dumas等《有机化学杂志》1988，53，4650的操作将该氯化物转化为胺。The amine is obtained by converting 3-(3-pyridyl)-1-propanol into the corresponding chloride according to the operation of B.Jursic et al. "Synthesis" 1988, (11), 868, and then through D.J.Dumas The operation of "Journal of Organic Chemistry" 1988, 53, 4650 converts the chloride into an amine.
3-[[5-(三氟甲基)-2-吡啶基]氧基]-1-丙胺
在氮下搅拌下，将2-氟-5-三氟甲基吡啶(1.831g，11mmol)溶于无水THF(15ml)，在冰浴中冷却至0℃。历时30分钟向其中滴加3-氨基-1-丙醇(0.76ml，10mmol)的无水THF(15ml)溶液和1M叔丁醇钾的THF溶液(10ml，10mmol)。搅拌该黄色溶液并使其缓慢温热至室温过夜。将反应混合物倒在水(75ml)中，用乙醚萃取(2×50ml)。将有机相用盐水(50ml)洗涤，干燥(Na2SO4)，过滤，在真空下蒸发，得到黄色液体，NMR和MS测定几乎是纯的，无需进一步纯化即可使用。2-Fluoro-5-trifluoromethylpyridine (1.831 g, 11 mmol) was dissolved in anhydrous THF (15 ml) with stirring under nitrogen and cooled to 0°C in an ice bath. To this was added dropwise a solution of 3-amino-1-propanol (0.76ml, 10mmol) in anhydrous THF (15ml) and a solution of 1M potassium tert-butoxide in THF (10ml, 10mmol) over 30 minutes. The yellow solution was stirred and allowed to warm slowly to room temperature overnight. The reaction mixture was poured into water (75ml) and extracted with ether (2 x 50ml). The organic phase was washed with brine (50ml), dried ( Na2SO4 ) , filtered and evaporated in vacuo to give a yellow liquid which was nearly pure by NMR and MS and used without further purification.
(+)-反式-1-羟基-2-氨基环戊烷氢溴酸盐 (+)-trans-1-hydroxy-2-aminocyclopentane hydrobromide
将(±)-反式-1-苄氧基-2-氨基环戊烷氢溴酸盐(8.2g，42.8mmol)用40％Hbr(60ml)处理。搅拌3天后，将溶液在真空中浓缩，得到7.09g(91％)氢溴酸盐，为橙色固体，1H-NMR(DMSO-d6)证实是纯的。(±)-trans-1-Benzyloxy-2-aminocyclopentane hydrobromide (8.2 g, 42.8 mmol) was treated with 40% Hbr (60 mL). After stirring for 3 days, the solution was concentrated in vacuo to afford 7.09 g (91%) of the hydrobromide salt as an orange solid, pure by 1 H-NMR (DMSO-d 6 ).
2，3-二氢-2，2-二甲基-1H-茚-1-胺按照世界专利WO 9927783的操作制备该胺。 2,3-Dihydro-2,2-dimethyl-1H-inden-1-amine The amine was prepared following the procedure of World Patent WO 9927783.
10-氨基-内-2，5-桥亚甲基二环并[4.4.0]癸-3-烯(56)10-Amino-endo-2,5-methanobicyclo[4.4.0]dec-3-ene (56)
如流程10所示制备该化合物。因而，将氯化铝(700mg，5.2mmol)加入到2-环己烯-1-酮(2.0g，20.8mmol)的甲苯(200ml)溶液中。40分钟后，加入新鲜蒸馏的环戊二烯(13.7g，208mmol)，加热至100℃达2小时。冷却后，将混合物用Et2O(300ml)稀释，用饱和NaHCO3(2×150ml)和盐水(100ml)洗涤。将合并后的有机层干燥(MgSO4)，过滤，浓缩。残余物经由快速色谱纯化，用50∶1己烷∶Et2O作为洗脱剂，得到2，5-桥亚甲基二环并[4.4.0]癸-3-烯-10-酮(54)的内(1.74g)与外(943mg)异构体，1H-NMR和GC/MS测定它们是纯的。This compound was prepared as shown in Scheme 10. Thus, aluminum chloride (700 mg, 5.2 mmol) was added to a solution of 2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (200 ml). After 40 minutes, freshly distilled cyclopentadiene (13.7 g, 208 mmol) was added and heated to 100° C. for 2 hours. After cooling, the mixture was diluted with Et2O (300ml), washed with saturated NaHCO3 (2 x 150ml) and brine (100ml). The combined organic layers were dried ( MgSO4 ), filtered and concentrated. The residue was purified by flash chromatography using 50:1 hexanes: Et2O as eluent to afford 2,5-methanobicyclo[4.4.0]dec-3-en-10-one (54 ) endo (1.74 g) and exo (943 mg) isomers, which were pure as determined by 1 H-NMR and GC/MS.
将乙酸钠(1.79g，21.8mmol)分批加入到内-2，5-桥亚甲基二环并[4.4.1]癸-3-烯-10-酮(54)(1.61g，9.9mmol)与盐酸羟胺(758mg，10.9mmol)的甲醇(33ml)溶液中，在室温下搅拌过夜。用H2O猝灭反应，用乙醚萃取(2×50ml)。将合并后的有机层干燥(MgSO4)，过滤，浓缩，得到内-2，5-桥亚甲基二环并[4.4.0]癸-3-烯-10-酮肟(55)，为糊状残余物，1H-NMR和GC/MS证实是纯的。Sodium acetate (1.79g, 21.8mmol) was added in portions to endo-2,5-methanobicyclo[4.4.1]dec-3-en-10-one (54) (1.61g, 9.9mmol ) and hydroxylamine hydrochloride (758mg, 10.9mmol) in methanol (33ml), stirred overnight at room temperature. The reaction was quenched with H2O and extracted with ether (2 x 50ml). The combined organic layers were dried ( MgSO4 ), filtered and concentrated to afford endo-2,5-methanobicyclo[4.4.0]dec-3-en-10-one oxime (55) as The pasty residue was pure by 1 H-NMR and GC/MS.
将内-2，5-桥亚甲基二环并[4.4.1]癸-3-烯-10-酮肟(55)(500mg，2.79mmol)溶于EtOAc(25ml)，加入10％ Pd/C(50mg)。在H2(40psi)下3小时后，将悬液通过C盐过滤，浓缩。将所得残余物溶于EtOH(25ml)，装入Raney-Ni(1.0g)。将悬液用NH3饱和，用H2(45psi)增压。6小时后，将悬液通过C盐过滤，用EtOAc(100ml)稀释，用饱和NaHCO3(100ml)洗涤。将合并后的有机层经MgSO4干燥，过滤，浓缩。1H-NMR和GC/MS揭示标题胺56是非对映体的2∶1混合物(418mg)。
10-氨基-4-(4’-甲基戊-3’-烯基)-二环并[4.4.0]癸-3-烯(59)10-amino-4-(4'-methylpent-3'-enyl)-bicyclo[4.4.0]dec-3-ene (59)
如流程11所示实现该化合物的制备。因而，将氯化铝(700mg，5.2mmol)加入到2-环己烯-1-酮(2.0g，20.8mmol)的甲苯(100ml)溶液中。40分钟后，加入月桂烯(17g，125mmol)，加热至100℃达2小时。冷却后，将混合物用Et2O(300ml)稀释，用饱和NaHCO3(2×150ml)和盐水(100ml)洗涤。将合并后的有机层经MgSO4干燥，过滤，浓缩。残余物经由快速色谱纯化，用50∶1己烷∶Et2O作为洗脱剂，得到4-(4’-甲基戊-3’-烯基)-二环并[4.4.0]癸-3-烯-10-酮(57)(2.55g)，1H-NMR和GC/MS证实是纯的。The preparation of this compound is accomplished as shown in Scheme 11. Thus, aluminum chloride (700 mg, 5.2 mmol) was added to a solution of 2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (100 ml). After 40 minutes, myrcene (17 g, 125 mmol) was added and heated to 100° C. for 2 hours. After cooling, the mixture was diluted with Et2O (300ml), washed with saturated NaHCO3 (2 x 150ml) and brine (100ml). The combined organic layers were dried over MgSO4 , filtered and concentrated. The residue was purified via flash chromatography using 50:1 hexane: Et2O as eluent to give 4-(4'-methylpent-3'-enyl)-bicyclo[4.4.0]dec- 3-en-10-one (57) (2.55 g) was confirmed to be pure by 1 H-NMR and GC/MS.
将乙酸钠(1.73g，21mmol)分批加入到4-(4’-甲基戊-3’-烯基)-二环并[4.4.0]癸-3-烯-10-酮(57)(2.23g，9.6mmol)与盐酸羟胺(733mg，10.5mmol)的甲醇(32ml)溶液中，在室温下搅拌过夜。用H2O猝灭反应，用乙醚萃取(2×50ml)。将合并后的有机层干燥(MgSO4)，过滤，浓缩，得到4-(4’-甲基戊-3’-烯基)-二环并[4.4.0]癸-3-烯-10-酮肟(58)，为糊状残余物，1H-NMR和GC/MS证实是纯的。Sodium acetate (1.73 g, 21 mmol) was added in portions to 4-(4'-methylpent-3'-enyl)-bicyclo[4.4.0]dec-3-en-10-one (57) (2.23g, 9.6mmol) and hydroxylamine hydrochloride (733mg, 10.5mmol) in methanol (32ml) were stirred overnight at room temperature. The reaction was quenched with H2O and extracted with ether (2 x 50ml). The combined organic layers were dried ( MgSO4 ), filtered and concentrated to give 4-(4'-methylpent-3'-enyl)-bicyclo[4.4.0]dec-3-ene-10- Ketoxime (58), as a pasty residue, was pure by 1 H-NMR and GC/MS.
将4-(4’-甲基戊-3’-烯基)-二环并[4.4.0]癸-3-烯-10-酮肟(600mg，2.42mmol)溶于EtOH(25ml)，加入10％Pd/C(1.0g)。将悬液用NH3饱和，用H2(45psi)增压。6小时后，将悬液通过C盐过滤，用EtOAc(100ml)稀释，用饱和NaHCO3(100ml)洗涤。将合并后的有机层经MgSO4干燥，过滤，浓缩。1H-NMR和GC/MS提示是纯的标题胺(550mg)。 4-(4'-Methylpent-3'-enyl)-bicyclo[4.4.0]dec-3-en-10-one oxime (600mg, 2.42mmol) was dissolved in EtOH (25ml), added 10% Pd/C (1.0 g). The suspension was saturated with NH3 and pressurized with H2 (45 psi). After 6 hours, the suspension was filtered through Celite® , diluted with EtOAc (100ml) and washed with saturated NaHCO3 (100ml). The combined organic layers were dried over MgSO4 , filtered and concentrated. 1 H-NMR and GC/MS indicated pure title amine (550mg).
2-氨基-7-呋喃基-3-甲基-4-苯并二氢吡喃酮盐酸盐(63)2-Amino-7-furyl-3-methyl-4-chromanone hydrochloride (63)
如流程12所示制备这种胺盐酸盐。因而，将7-三氟甲磺酸-3-甲基-4-苯并二氢吡喃酮(3.0g，9.7mmol)(按照K.Koch和M.S.Biggers《有机化学杂志》1994，59，1216的操作制备)加入到2-(三丁基甲锡烷基)呋喃(3.79g，10.6mmol)、Pd(PPh3)4(223mg，0.19mmol)、LiCl(1.23g，29.0mmol)与两粒2，6-二叔丁基-4-甲基苯酚晶体的1，4-二噁烷(50ml)溶液中，加热至回流达12小时。冷却后，用饱和NH4Cl(40ml)猝灭混合物，用Et2O萃取(2×50ml)。将合并后的有机层经MgSO4干燥，过滤，浓缩。残余物经由快速色谱纯化，用20∶1己烷∶EtOAc作为洗脱剂，得到7-呋喃基-3-甲基-4-苯并二氢吡喃酮(60)(1.78g)，为黄色固体，m.p.94-95℃。This amine hydrochloride was prepared as shown in Scheme 12. Thus, 7-trifluoromethanesulfonic acid-3-methyl-4-chromanone (3.0 g, 9.7 mmol) (according to K.Koch and MS Biggers "Journal of Organic Chemistry" 1994,59,1216 Operation preparation) was added to 2-(tributylstannyl)furan (3.79g, 10.6mmol), Pd(PPh3)4(223mg, 0.19mmol), LiCl (1.23g, 29.0mmol) and two grains of 2,6- A solution of crystals of di-tert-butyl-4-methylphenol in 1,4-dioxane (50ml) was heated to reflux for 12 hours. After cooling, the mixture was quenched with saturated NH4Cl (40ml) and extracted with Et2O (2x50ml). The combined organic layers were dried over MgSO4 , filtered and concentrated. The residue was purified via flash chromatography using 20:1 hexanes:EtOAc as eluent to give 7-furyl-3-methyl-4-chromanone (60) (1.78 g) as yellow Solid, mp 94-95°C.
将乙酸钠(395mg，4.85mmol)分批加入到7-呋喃基-3-甲基-4-苯并二氢吡喃酮(60)(500mg，2.19mmol)与盐酸羟胺(167mg，2.41mmol)的甲醇(5ml)溶液中，在室温下搅拌过夜。用H2O猝灭反应，用乙醚萃取(2×25ml)。将合并后的有机层干燥(MgSO4)，过滤，浓缩，得到7-呋喃基-3-甲基-4-苯并二氢吡喃酮肟(61)，为白色固体，m.p.175-177℃。Sodium acetate (395mg, 4.85mmol) was added in portions to 7-furyl-3-methyl-4-chromanone (60) (500mg, 2.19mmol) and hydroxylamine hydrochloride (167mg, 2.41mmol) methanol (5ml) and stirred overnight at room temperature. The reaction was quenched with H2O and extracted with ether (2 x 25ml). The combined organic layers were dried ( MgSO4 ), filtered and concentrated to afford 7-furyl-3-methyl-4-chromanone oxime (61) as a white solid, mp 175-177°C.
将甲苯磺酰氯(397mg，2.08mmol)加入到0℃的7-呋喃基-3-甲基-4-苯并二氢吡喃酮肟(61)(461mg，1.89mmol)与吡啶(0.5ml)的CH2Cl2(10ml)溶液中。6小时后，将混合物用CH2Cl2(30ml)稀释，用5％HCl(20ml)洗涤。将有机层经MgSO4干燥，过滤，浓缩。残余物经由快速色谱纯化，用5∶1己烷∶EtOAc作为洗脱剂，得到7-呋喃基-3-甲基-4-苯并二氢吡喃酮O-(甲苯磺酰基)-肟(62)(429mg)，为粉红色固体，m.p.163-164℃(分解)。Tosyl chloride (397mg, 2.08mmol) was added to 7-furyl-3-methyl-4-chromanone oxime (61) (461mg, 1.89mmol) and pyridine (0.5ml) at 0°C CH 2 Cl 2 (10ml) solution. After 6 hours, the mixture was diluted with CH2Cl2 ( 30ml ) and washed with 5% HCl (20ml). The organic layer was dried over MgSO4 , filtered and concentrated. The residue was purified via flash chromatography using 5:1 hexanes:EtOAc as eluent to afford 7-furyl-3-methyl-4-chromanone O-(tosyl)-oxime ( 62) (429 mg), a pink solid, mp 163-164°C (decomposition).
将乙醇钠的乙醇溶液(0.35ml，2.87M，1.0mmol)加入到搅拌着的7-呋喃基-3-甲基-4-苯并二氢吡喃酮-O-(甲苯磺酰基)-肟(62)(410mg，1.0mmol)的苯(4ml)溶液中。18小时后，加入3N HCl(6ml)，分离各层。有机层进一步用3N HCl萃取(2×10ml)，浓缩合并后的含水萃取液，得到粗的标题化合物63，为橙色固体(388mg)，无需进一步纯化即可使用。 Sodium ethoxide in ethanol (0.35ml, 2.87M, 1.0mmol) was added to the stirred 7-furyl-3-methyl-4-chromanone-O-(tosyl)-oxime (62) (410 mg, 1.0 mmol) in benzene (4 ml). After 18 hours, 3N HCl (6ml) was added and the layers were separated. The organic layer was further extracted with 3N HCl (2 x 10ml) and the combined aqueous extracts were concentrated to give crude title compound 63 as an orange solid (388mg) which was used without further purification.
2-氨基-7-(3’-甲氧基丙炔基)-3-甲基-4-苯并二氢吡喃酮盐酸盐(65)2-Amino-7-(3'-methoxypropynyl)-3-methyl-4-chromanone hydrochloride (65)
如流程13所示制备该胺盐酸盐。因而，将7-三氟甲磺酸-3-甲基-4-苯并二氢吡喃酮(3.10g，10mmol)(按照K.Koch和M.S.Biggers《有机化学杂志》1994，59，1216的操作制备)加入到甲基炔丙基醚(1.05g，15mmol)、(Ph3P)4Pd(210mg，0.30mmol)与Et3N(6ml)的DMF(30ml)溶液中，在70℃下加热1小时。冷却后，用饱和NH4Cl(40ml)猝灭混合物，用Et2O萃取(2×50ml)。将合并后的有机层经MgSO4干燥，过滤，浓缩。残余物经由快速色谱纯化，用9∶1己烷-EtOAc作为洗脱剂，得到7-(3’-甲氧基丙炔基)-3-甲基-4-苯并二氢吡喃酮(64)(1.40g)，为白色固体，m.p.60-63℃。The amine hydrochloride was prepared as shown in Scheme 13. Thus, 7-trifluoromethanesulfonic acid-3-methyl-4-chromanone (3.10g, 10mmol) (according to the operation of K.Koch and MSBiggers "Journal of Organic Chemistry" 1994,59,1216 Preparation) was added to a DMF (30ml) solution of methyl propargyl ether (1.05g, 15mmol), (Ph 3 P) 4 Pd (210mg, 0.30mmol) and Et 3 N (6ml), heated at 70°C 1 hour. After cooling, the mixture was quenched with saturated NH4Cl (40ml) and extracted with Et2O (2x50ml). The combined organic layers were dried over MgSO4 , filtered and concentrated. The residue was purified via flash chromatography using 9:1 hexane-EtOAc as eluent to afford 7-(3'-methoxypropynyl)-3-methyl-4-chromanone ( 64) (1.40 g), as a white solid, mp 60-63°C.
按照如上关于2-氨基-7-呋喃基-3-甲基-4-苯并二氢吡喃酮盐酸盐所述相同方式实现64向标题化合物65的转化。
2-氨基-α-四氢萘酮盐酸盐(66)2-Amino-α-tetralone hydrochloride (66)
通过如上关于2-氨基-7-呋喃基-3-甲基-4-苯并二氢吡喃酮盐酸盐所述相同操作如流程14所示从α-四氢萘酮得到该化合物。
2-氨基-内-6，9-桥亚乙基二环并[4.4.0]癸-7-烯酮盐酸盐(70)2-Amino-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone hydrochloride (70)
如流程15所示制备该胺盐酸盐。因而，将氯化铝(700mg，5.2mmol)加入到2-环己烯-1-酮(2.0g，20.8mmol)的甲苯(100ml)溶液中。40分钟后，加入环己二烯(8.3g，104mmol)，加热至100℃达2小时。冷却后，将混合物用Et2O(300ml)稀释，用饱和NaHCO3(2×150ml)和盐水(100ml)洗涤。将合并后的有机层经MgSO4干燥，过滤，浓缩。残余物经由快速色谱纯化，用50∶1己烷∶Et2O作为洗脱剂，得到内-2，5-桥亚乙基二环并[4.4.0]癸-7-烯-10-酮(67)(2.77g)，1H-NMR和GC/MS证实是纯的。The amine hydrochloride was prepared as shown in Scheme 15. Thus, aluminum chloride (700 mg, 5.2 mmol) was added to a solution of 2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (100 ml). After 40 minutes, cyclohexadiene (8.3 g, 104 mmol) was added and heated to 100° C. for 2 hours. After cooling, the mixture was diluted with Et2O (300ml), washed with saturated NaHCO3 (2 x 150ml) and brine (100ml). The combined organic layers were dried over MgSO4 , filtered and concentrated. The residue was purified via flash chromatography using 50:1 hexane: Et2O as eluent to afford endo-2,5-ethanobicyclo[4.4.0]dec-7-en-10-one (67) (2.77 g), 1 H-NMR and GC/MS proved pure.
将内-2，5-桥亚乙基二环并[4.4.0]癸-7-烯-10-酮(67)(2.17g，12.3mmol)的THF(20ml)溶液加入到-78℃的LDA的THF(30ml)溶液(6.7ml，2.0M，13.5mmol)中。45分钟后，加入三甲基甲硅烷基氯(2.0g，18.5mmol)，使混合物缓慢温热至0℃。将混合物用饱和NaHCO3溶液(30ml)稀释，用Et2O萃取(2×30ml)，干燥(MgSO4)，浓缩。将残余物溶于THF(60ml)，分批加入N-溴琥珀酰亚胺(2.6g，14.7mmol)。30分钟后，将混合物用饱和NH4Cl溶液(30ml)稀释，用Et2O萃取(2×40ml)。将合并后的有机层干燥(MgSO4)并浓缩。残余物经由快速色谱纯化，用33∶1己烷-Et2O作为洗脱剂，得到2-溴-内-6，9-桥亚乙基二环并[4.4.0]癸-7-烯酮(68)(1.44g)，为浅黄色油，1H-NMR和GC/MS证实是纯的。A solution of endo-2,5-ethanobicyclo[4.4.0]dec-7-en-10-one (67) (2.17g, 12.3mmol) in THF (20ml) was added to a -78°C LDA in THF (30ml) (6.7ml, 2.0M, 13.5mmol). After 45 minutes, trimethylsilyl chloride (2.0 g, 18.5 mmol) was added and the mixture was allowed to warm slowly to 0°C. The mixture was diluted with saturated NaHCO3 solution (30ml), extracted with Et2O (2x30ml), dried ( MgSO4 ) and concentrated. The residue was dissolved in THF (60ml), and N-bromosuccinimide (2.6g, 14.7mmol) was added portionwise. After 30 minutes, the mixture was diluted with saturated NH4Cl solution (30ml) and extracted with Et2O (2x40ml). The combined organic layers were dried ( MgSO4 ) and concentrated. The residue was purified via flash chromatography using 33:1 hexane- Et2O as eluent to give 2-bromo-endo-6,9-ethanobicyclo[4.4.0]dec-7-ene Ketone (68) (1.44 g), as a light yellow oil, was pure by 1 H-NMR and GC/MS.
将叠氮化钠(280mg，4.3mmol)加入到2-溴-内-6，9-桥亚乙基二环并[4.4.0]癸-7-烯酮(68)(850mg，3.9mmol)的DMF(20ml)溶液中。2小时后，将混合物用水(30ml)稀释，用Et2O萃取(2×40ml)。将合并后的有机层干燥(MgSO4)并浓缩。残余物经由快速色谱纯化，用20∶1己烷-Et2O作为洗脱剂，得到2-叠氮基-内-6，9-桥亚乙基二环并[4.4.0]癸-7-烯酮(69)(469mg)，为一种油，1H-NMR证实是纯的。Sodium azide (280 mg, 4.3 mmol) was added to 2-bromo-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone (68) (850 mg, 3.9 mmol) DMF (20ml) solution. After 2 hours, the mixture was diluted with water (30ml) and extracted with Et2O (2x40ml). The combined organic layers were dried ( MgSO4 ) and concentrated. The residue was purified via flash chromatography using 20:1 hexane- Et2O as eluent to give 2-azido-endo-6,9-ethanobicyclo[4.4.0]dec-7 -Enone (69) (469 mg) as an oil, pure by 1 H-NMR.
将三苯膦(486mg，1.85mmol)加入到2-叠氮基-内-6，9-桥亚乙基二环并[4.4.0]癸-7-烯酮(69)(310mg，1.42mmol)的THF(10ml)与水(1ml)溶液中。搅拌12小时后，将混合物用6N HCl(10ml)稀释，分离各层。有机相用6N HCl萃取(2×5ml)，将合并后的含水层浓缩至干，得到所需的标题化合物70，为浓稠的橙色的油(500mg)，其1H-NMR(DMSO-d6)与指定结构是一致的。Triphenylphosphine (486 mg, 1.85 mmol) was added to 2-azido-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone (69) (310 mg, 1.42 mmol ) in THF (10ml) and water (1ml). After stirring for 12 hours, the mixture was diluted with 6N HCl (10 ml) and the layers were separated. The organic phase was extracted with 6N HCl (2 x 5 ml) and the combined aqueous layers were concentrated to dryness to afford the desired title compound 70 as a thick orange oil (500 mg) with 1 H-NMR (DMSO-d 6 ) It is consistent with the specified structure.
内-2-氨基降冰片烷-5-羧酸异丙酯(71)和内-2-氨基降冰片烷-6-羧酸异丙酯(72)按照前述相同方式(见流程9)从降冰片-2-烯-5-羧酸异丙酯制备这些胺。Isopropyl endo-2-aminonorbornane-5-carboxylate (71) and isopropyl endo-2-aminonorbornane-6-carboxylate (72) These amines were prepared from isopropyl norbornan-2-ene-5-carboxylate in the same manner as previously described (see Scheme 9).
关于酮被还原性胺化为胺的通用操作A general procedure for the reductive amination of ketones to amines
在氮气氛下的干燥烧瓶内，将酮(1mmol)、乙酸铵(20mmol)和3A分子筛(2.8重量当量)混合在无水甲醇中。加入氰基硼氢化钠(4mmol)，将所得混合物在室温下搅拌，直至TLC分析显示原料酮消失。在真空下从反应混合物中汽提甲醇，将残余物溶于6N HCl。搅拌15分钟后，用二乙醚萃取除去非碱性物质。用50％含水NaOH小心地升高含水相的pH至～8，用EtOAc萃取胺(3次)。将EtOAc萃取液合并，用盐水洗涤，干燥(Na2SO4)，过滤，浓缩，得到相应的胺。粗胺一般是纯的，无需进一步纯化即可使用。The ketone (1 mmol), ammonium acetate (20 mmol) and 3A molecular sieves (2.8 weight equivalents) were mixed in anhydrous methanol in a dry flask under nitrogen atmosphere. Sodium cyanoborohydride (4 mmol) was added and the resulting mixture was stirred at room temperature until TLC analysis showed disappearance of the starting ketone. Methanol was stripped from the reaction mixture under vacuum and the residue was dissolved in 6N HCl. After stirring for 15 minutes, the non-basic material was removed by extraction with diethyl ether. The pH of the aqueous phase was carefully raised to ~8 with 50% aqueous NaOH and the amine was extracted with EtOAc (3x). The EtOAc extracts were combined, washed with brine, dried ( Na2SO4 ), filtered and concentrated to give the corresponding amine . The crude amine is generally pure and used without further purification.
关于胺的BOC-去保护的通用操作General procedure for BOC-deprotection of amines
向冰冷的BOC-保护的胺(1mmol)的无水CH2Cl2(1ml)溶液中加入三乙基硅烷(0.5ml)和三氟乙酸(1ml)。通过原料的消失(5分钟至1.5小时)监测反应进展。将反应混合物用甲苯稀释，浓缩。将残余物溶于水(10ml)和EtOAc(20ml)，调节pH至～8(含水NaHCO3)，分离有机相。含水相用EtOAc萃取(2×15ml)。将有机相合并，用盐水洗涤，干燥(Na2SO4)，过滤，浓缩，得到胺。To an ice-cold solution of the BOC-protected amine (1 mmol) in anhydrous CH2Cl2 (1 ml ) was added triethylsilane (0.5 ml) and trifluoroacetic acid (1 ml). Reaction progress was monitored by disappearance of starting material (5 minutes to 1.5 hours). The reaction mixture was diluted with toluene and concentrated. The residue was dissolved in water (10ml) and EtOAc (20ml), the pH was adjusted to ~8 (aq. NaHCO3 ), and the organic phase was separated. The aqueous phase was extracted with EtOAc (2 x 15ml). The organic phases were combined, washed with brine, dried ( Na2SO4 ), filtered and concentrated to give the amine.
胺73和74的制备
经由上述标准的还原性胺化条件，从相应的已知的酮二内酯(《有机化学杂志》1998，63，9889-94)制备这些胺。1H、13C NMR和IR光谱与指定结构是一致的。
胺77和78的制备Preparation of Amines 77 and 78
这些胺的制备如流程16所示。按照《有机化学杂志》1998，63，9889-94的操作制备大环二内酯 75。因而，在上述参考文献所报道的标准大环内酯化条件下，使N-t-BOC-天冬氨酸(2.33g)与2-氯甲基-3-氯丙烯(1.25g)和Cs2CO3(7.0g)在DMF(1000ml)中反应，得到1.12g(收率40％) 75，为玻璃状固体。质谱(EI-)显示[M-1]+在(m/e)284，而1H、13C NMR和IR光谱与75的结构是一致的。The preparation of these amines is shown in Scheme 16. The macrocyclic dilactone 75 was prepared according to the procedure of "Journal of Organic Chemistry" 1998, 63, 9889-94. Thus, Nt-BOC-aspartic acid (2.33 g) was reacted with 2-chloromethyl-3-chloropropene (1.25 g) and Cs2CO 3 (7.0 g) was reacted in DMF (1000 ml) to obtain 1.12 g (40% yield) 75 as a glassy solid. Mass spectrum (EI-) showed [M-1] + at (m/e) 284, while 1 H, 13 C NMR and IR spectra were consistent with the structure of 75.
向烯烃 75(288mg，1.01mmol)的无水EtOAc(6ml)溶液中加入10％Pd/碳(60mg)。将所得混合物用氮净化，在45psi氢压下的Parr氢化器内搅拌2.5小时。将反应混合物用氮净化，过滤，浓缩。残余物经过快速柱色谱纯化(硅胶，己烷-EtOAc的7∶3混合物)，得到91mg(收率32％)还原产物76。1H、13C NMR和IR光谱与 76的结构是一致的。To a solution of olefin 75 (288 mg, 1.01 mmol) in anhydrous EtOAc (6 ml) was added 10% Pd/carbon (60 mg). The resulting mixture was purged with nitrogen and stirred in a Parr hydrogenator at 45 psi of hydrogen for 2.5 hours. The reaction mixture was purged with nitrogen, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 7:3 mixture of hexane-EtOAc) to afford 91 mg (32% yield) of the reduced product 76. 1 H, 13 C NMR and IR spectra are consistent with the structure of 76 .
按照前述通用的BOC-去保护操作除去
75和
76中的BOC保护基团，分别得到相应的胺
77和
78。1H、13C NMR和IR光谱与指定结构是一致的。
苯基二内酯81的合成Synthesis of Phenyl Dilactone 81
该化合物的制备如流程17所示。在氮下，历时30分钟向冰冷(0℃)的充分搅拌着的苯基琥珀酸(0.923g，5.2mmol)与DMAP(0.064g，0.52mmol)的无水CH2Cl2(55ml)溶液中滴加BOC-丝氨醇溶液(《合成》1998，1113-1118)(1.0g，5.2mmol)。使所得混合物缓慢温热至室温，搅拌另外12小时，用CH2Cl2(40ml)稀释，用饱和含水碳酸氢钠萃取(3×10ml)。将碱性萃取液合并，小心地用2N HCl酸化，用EtOAc萃取(3×20ml)。将合并后的EtOAc萃取液用盐水洗涤，干燥(Na2SO4)，过滤，浓缩，得到白色泡沫(1.7g)。1H NMR显示是酸 79的1∶1非对映体混合物。The preparation of this compound is shown in Scheme 17. To an ice-cold (0° C.) well stirred solution of phenylsuccinic acid (0.923 g, 5.2 mmol) and DMAP (0.064 g, 0.52 mmol) in anhydrous CH 2 Cl 2 (55 ml) under nitrogen over 30 min BOC-serinol solution ("Synthesis" 1998, 1113-1118) (1.0 g, 5.2 mmol) was added dropwise. The resulting mixture was allowed to warm slowly to room temperature, stirred for a further 12 hours, diluted with CH2Cl2 ( 40ml ) and extracted with saturated aqueous sodium bicarbonate (3 x 10ml). The basic extracts were combined, carefully acidified with 2N HCl and extracted with EtOAc (3 x 20ml). The combined EtOAc extracts were washed with brine, dried ( Na2SO4 ), filtered and concentrated to give a white foam (1.7g). 1 H NMR showed a 1:1 mixture of diastereomers of acid 79 .
历时3小时向充分搅拌着的冰冷的酸 79(1.00g，2.72mmol)与三苯膦(786mg，3.0mmol)的无水THF(122ml)悬液中滴加偶氮二羧酸二乙酯(0.52g，3.0mmol)的THF(55ml)溶液。使所得混合物缓慢温热至室温，搅拌另外5小时，浓缩至约5ml。残余混合物用EtOAc(50ml)和水(20ml)稀释。分离有机相，用含水NaHCO3(10ml)、盐水(10ml)洗涤，干燥(Na2SO4)，过滤，浓缩，得到油性残余物。快速色谱纯化(硅胶，己烷)得到228mg(收率22％)二内酯80的1∶1混合物，m.p.＝161-162℃。质谱(EI)显示M+在m/e 349。To a well stirred ice-cold suspension of acid 79 (1.00 g, 2.72 mmol) and triphenylphosphine (786 mg, 3.0 mmol) in anhydrous THF (122 ml) was added dropwise diethyl azodicarboxylate ( 0.52g, 3.0mmol) in THF (55ml). The resulting mixture was allowed to warm slowly to room temperature, stirred for an additional 5 hours, and concentrated to about 5 ml. The residual mixture was diluted with EtOAc (50ml) and water (20ml). The organic phase was separated, washed with aqueous NaHCO3 (10ml) , brine (10ml), dried ( Na2SO4 ), filtered and concentrated to an oily residue. Purification by flash chromatography (silica gel, hexanes) afforded 228 mg (22% yield) of a 1:1 mixture of dilactone 80, mp = 161-162°C. Mass spectrum (EI) showed M + at m/e 349.
在前述标准的BOC去保护条件下除去BOC保护基团，得到胺 81。 Removal of the BOC protecting group under the standard BOC deprotection conditions previously described affords amine 81 .
二内酯胺 84和 85的合成Synthesis of Dilactone Amines 84 and 85
这些化合物的制备如流程18所示。向搅拌着的丝氨醇(3.0g，15.7mmol)、吡啶(1.24g，0.98mol)与DMAP(0.19g，1.57mmol)的无水CH2Cl2(140ml)溶液中滴加N-CBz天冬氨酸酐(3.52g，14.13mmol)的无水THF(20ml0溶液。在室温下搅拌2小时后，将反应混合物浓缩至体积约10ml，用EtOAc(100ml)和水(30ml)稀释。调节pH至8.5(含水NaHCO3)，将含水相分离，用2N HCl酸化至pH3，用EtOAc萃取(3×20ml)。将合并后的有机萃取液用盐水洗涤，干燥(Na2SO4)，过滤，浓缩，得到5.8g 82，为泡沫状白色物质。1H NMR光谱显示它是相当纯的，含有非对映体的混合物。The preparation of these compounds is shown in Scheme 18. To the stirring serinol (3.0g, 15.7mmol), pyridine (1.24g, 0.98mol) and DMAP (0.19g, 1.57mmol) in anhydrous CH 2 Cl 2 (140ml) solution was added dropwise N-CBz day Aspartic anhydride (3.52 g, 14.13 mmol) was dissolved in anhydrous THF (20 ml). After stirring at room temperature for 2 hours, the reaction mixture was concentrated to a volume of about 10 ml and diluted with EtOAc (100 ml) and water (30 ml). The pH was adjusted to 8.5 (aq. NaHCO 3 ), the aqueous phase was separated, acidified to pH 3 with 2N HCl, extracted with EtOAc (3 x 20 ml). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated , yielding 5.8 g of 82 as a foamy white material.1H NMR spectrum showed it to be fairly pure , containing a mixture of diastereomers.
历时3小时向三苯膦(3.60g，13.75mmol)与1，3-二异丙基碳二亚胺(2.80g，13.75mmol)的无水THF(1.15L)溶液中滴加酸82(5.5g，12.5mmol)的无水THF(100ml)溶液。将所得混合物搅拌另外6小时，在真空中浓缩至体积约20ml，用乙醚(200ml)和水(100ml)稀释。分离有机相，用5％含水NaHCO3和盐水洗涤，干燥(Na2SO4)，过滤，在真空中浓缩。油性残余物经过快速柱色谱纯化，得到1.3g(收率23％)所需的二内酯83。质谱(ES-)显示m/e为421(M-1)+。1H、13C NMR和IR光谱与结构83是一致的。Acid 82 (5.5 g, 12.5 mmol) in anhydrous THF (100 ml). The resulting mixture was stirred for a further 6 hours, concentrated in vacuo to a volume of about 20ml, diluted with ether (200ml) and water (100ml). The organic phase was separated, washed with 5 % aqueous NaHCO3 and brine, dried ( Na2SO4 ), filtered and concentrated in vacuo. The oily residue was purified by flash column chromatography to afford 1.3 g (23% yield) of the desired dilactone 83. Mass spectrum (ES-) showed m/e of 421(M-1) + . 1 H, 13 C NMR and IR spectra were consistent with structure 83.
在标准的BOC去保护条件下去保护二内酯83，得到胺84。Deprotection of the dilactone 83 under standard BOC deprotection conditions affords the amine 84.
向N-CBz-保护的二内酯83(200mg，0.47mmol)的EtOAc(10ml)溶液中加入10％ Pd/C(40mg)，将所得混合物在氢气的气囊压力下搅拌12小时。将反应混合物用N2净化，通过多孔玻璃漏斗过滤，浓缩，得到胺85(126mg)。该粗胺无需进一步纯化即可使用。流程19
胺86和88的制备Preparation of Amines 86 and 88
2，6，6-三甲基-2，4-环庚二烯基胺(86)和2，3，6，6-四甲基-3-环庚烯酮(87)的合成如流程19所示，后者是胺88的前体。因而，利用《合成快报》1999，1781所述的异丙醇钛/NaBH4/Et3N-介导的还原性胺化操作，优黄蒿萜酮(《加拿大化学杂志》1974，52，1352)容易转化为相应的胺86。利用《四面体快报》1995，51，743-754所述操作，向优黄蒿萜酮进行三甲基铝的Cu(I)-催化的迈克尔加成，得到2，3，5，5-四甲基-3-环庚烯酮(87)。按照世界专利WO 9927783的通用操作，后者转化为2，3，5，5-四甲基-2-环庚烯基胺(88)。N-甲基-N-(2-苯乙基)-(1，5，5-三甲基-3-氨基环己基)脲(89) 2,6,6-trimethyl-2,4-cycloheptadienylamine (86) and 2,3,6,6-tetramethyl-3-cycloheptenone (87) are synthesized as shown in Scheme 19 The latter is the precursor of amine 88, as shown. Thus, using the titanium isopropoxide/NaBH 4 /Et 3 N-mediated reductive amination operation described in "Synthetic Letters" 1999, 1781, artemisinone ("Canadian Chemical Journal" 1974, 52, 1352 ) is readily converted to the corresponding amine 86. Using the procedure described in Tetrahedron Letters 1995, 51, 743-754, Cu(I)-catalyzed Michael addition of trimethylaluminum to euartemisinone affords 2,3,5,5-tetra Methyl-3-cycloheptenone (87). Following the general procedure of World Patent WO 9927783, the latter is converted to 2,3,5,5-tetramethyl-2-cycloheptenylamine (88). N-Methyl-N-(2-phenylethyl)-(1,5,5-trimethyl-3-aminocyclohexyl)urea (89)
利用标准的HOAt、EDCI与DMAP-介导的偶联条件，使1，5，5-三甲基-3-氧代-1-环己基羧酸(M.S.Ziegler和R.M.Herbst《有机化学杂志》1951，16，920)与N-甲基-2-苯基乙胺偶联，得到[N-甲基-N-(2-苯乙基)]-1，5，5-三甲基-3-氧代-1-环己基甲酰胺，为淡黄色油。质谱显示母体离子在m/e 301。1H和13C NMR光谱与这种结构是一致的。Using standard HOAt, EDCI and DMAP-mediated coupling conditions, 1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (MS Ziegler and RM Herbst "Journal of Organic Chemistry" 1951, 16 , 920) coupled with N-methyl-2-phenylethylamine to give [N-methyl-N-(2-phenylethyl)]-1,5,5-trimethyl-3-oxo -1-cyclohexylformamide, pale yellow oil. Mass spectrum showed the parent ion at m/e 301. 1 H and 13 C NMR spectra were consistent with this structure.
按照世界专利WO 9927783的通用操作从该酮制备胺89如下，转化为相应的N-羟基肟，然后在RaneyNi的存在下氢化。胺的1H NMR显示是非对映体的1∶1混合物。Amine 89 was prepared from this ketone following the general procedure of World Patent WO 9927783 by conversion to the corresponding N-hydroxyoxime followed by hydrogenation in the presence of Raney® Ni. 1 H NMR of the amine showed a 1:1 mixture of diastereomers.
3-(3，3-二甲基丁氧羰基)-3，5，5-三甲基环己胺(90)
在标准的偶联条件下，将1，5，5-三甲基-3-氧代-1-环己基羧酸(M.S.Ziegler和R.M.Herbst《有机化学杂志》1951，16，920)用3，3-二甲基戊醇(1.84g)、DMAP(2.21g)和1，3-二异丙基碳二亚胺(2.17g)的CH2Cl2(80ml)溶液处理，得到2.41g(收率55％)3-(3，3-二甲基丁氧羰基)-3，5，5-三甲基环己烷酮。质谱(EI)显示母体离子在m/e 268。Under standard coupling conditions, 1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (MS Ziegler and RM Herbst "Journal of Organic Chemistry" 1951,16,920) was mixed with 3,3- Treatment of dimethylpentanol (1.84g), DMAP (2.21g) and 1,3-diisopropylcarbodiimide (2.17g) in CH2Cl2 ( 80ml ) afforded 2.41g (yield 55 %) 3-(3,3-Dimethylbutoxycarbonyl)-3,5,5-trimethylcyclohexanone. Mass spectrum (EI) showed the parent ion at m/e 268.
按照世界专利WO 9927783的通用操作将该酮转化为标题胺90如下，转化为相应的肟，然后在RaneyNi的存在下氢化。胺90的1H NMR显示是非对映体的1∶1混合物。 Following the general procedure of World Patent No. WO 9927783 the ketone is converted to the title amine 90 as follows, converted to the corresponding oxime and then hydrogenated in the presence of Raney (R) Ni. 1 H NMR of amine 90 showed a 1:1 mixture of diastereomers.
4-(4，6-双-三氟甲基-2-吡啶基)氧基-3，3，5，5-四甲基环己胺(93)4-(4,6-bis-trifluoromethyl-2-pyridyl)oxy-3,3,5,5-tetramethylcyclohexylamine (93)
该胺的合成如流程20所示。因而，将4-羟基-3，3，5，5-四甲基环己基-1，1-乙二醇乙缩醛(900mg，4.2mmol)溶于无水DMF(8.4ml)，将混合物冷却至0℃，加入35％(wt)KH的油悬液(591mg，5.04mmol)。将混合物搅拌1小时后，滴加2-氯-4，6-双-三氟甲基-2-吡啶(1.48g，6.3mmol)的DMF(2ml)溶液。将混合物在0℃下搅拌1小时，然后在室温下搅拌12小时，用氯化铵小心地猝灭。加入二乙醚(100ml)，分离有机相，用盐水洗涤，干燥(MgSO4)，浓缩得到深褐色固体。从热己烷中重结晶，得到950mg(收率53％)4-(4，6-双-三氟甲基-2-吡啶基)氧基-3，3，5，5-四甲基环己基-1，1-乙二醇乙缩醛(91)，m.p.＝105-106℃。The synthesis of this amine is shown in Scheme 20. Thus, 4-hydroxy-3,3,5,5-tetramethylcyclohexyl-1,1-ethanediol acetal (900 mg, 4.2 mmol) was dissolved in anhydrous DMF (8.4 ml), and the mixture was cooled To 0°C, 35% (wt) KH in oil (591 mg, 5.04 mmol) was added. After the mixture was stirred for 1 hour, a solution of 2-chloro-4,6-bis-trifluoromethyl-2-pyridine (1.48 g, 6.3 mmol) in DMF (2 ml) was added dropwise. The mixture was stirred at 0 °C for 1 hour, then at room temperature for 12 hours, carefully quenched with ammonium chloride. Diethyl ether (100ml) was added and the organic phase was separated, washed with brine, dried ( MgSO4 ) and concentrated to give a dark brown solid. Recrystallization from hot hexane afforded 950 mg (53% yield) of 4-(4,6-bis-trifluoromethyl-2-pyridyl)oxy-3,3,5,5-tetramethylcyclo Hexyl-1,1-ethanediol acetal (91), mp=105-106°C.
将乙缩醛(91)(900mg)溶于THF、二噁烷与2N HCl的1∶1∶1混合物(30ml)，将所得溶液在室温下搅拌12小时，此时GC显示原料完全消失。混合物用水和二乙醚(各50ml)稀释，分离有机相，用盐水洗涤，干燥(Na2SO4)，浓缩，得到油性残余物。该残余物经过硅胶色谱纯化(己烷-EtOAc，5∶1)，得到712mg(收率96％)酮92，为无色的油。质谱(EI)显示母体离子在m/e 383。Acetal (91) (900mg) was dissolved in a 1:1:1 mixture of THF, dioxane and 2N HCl (30ml) and the resulting solution was stirred at room temperature for 12 hours at which time GC showed complete disappearance of starting material. The mixture was diluted with water and diethyl ether (50ml each), the organic phase was separated, washed with brine, dried ( Na2SO4 ) and concentrated to give an oily residue . The residue was purified by chromatography on silica gel (hexane-EtOAc, 5:1) to afford 712 mg (96% yield) of ketone 92 as a colorless oil. Mass spectrum (EI) showed the parent ion at m/e 383.
按照世界专利WO 9927783的通用操作实现92的还原性胺化，得到标题胺93。 Reductive amination of 92 was achieved following the general procedure of World Patent WO 9927783 to afford the title amine 93.
3-(2，3-二氯丙氧基)甲基-3，5，5-三甲基环己胺(97)3-(2,3-dichloropropoxy)methyl-3,5,5-trimethylcyclohexylamine (97)
胺97的合成如流程21所示。按照《四面体快报》1991，32，1831-4的操作进行烯烃94的二氯化作用，得到乙缩醛95。将后者(500mg)溶于THF与2N HCl的1∶1混合物。将所得溶液在室温下搅拌1小时，此时TLC显示原料已经消失。混合物用EtOAc和水(各30ml)稀释，分离有机相，用盐水洗涤，干燥(Na2SO4)，过滤，浓缩，得到383mg酮96，为一种油。1H-NMR与异构体的非对映体混合物是一致的。按照前述标准操作进行还原性胺化，得到标题胺97。
5β-(2-苯乙基)-3β-甲氧基-4β-甲基-4-硝基环己胺(105)5β-(2-phenylethyl)-3β-methoxy-4β-methyl-4-nitrocyclohexylamine (105)
胺105的制备如流程23所示。按照《日本化学会通报》1968，41，1441的操作使硝基乙烷与二氢肉桂醛缩合，得到相应的硝基醇101。按照《合成》1982，1017的操作进行101的脱水，然后在聚合物载体上进行三苯膦-介导的异构化(《四面体快报》1998，39，811-812)，得到烯烃103。按照《四面体快报》2000，41，1717的操作向Danishefsky二烯进行103的狄尔斯-阿德耳环加成，得到酮104。按照世界专利WO 9927783的标准操作将酮104转化为胺105。
3-氰基-3，5，5-三甲基环己胺(106)3-cyano-3,5,5-trimethylcyclohexylamine (106)
按照上述标准的还原性胺化操作，通过3-氰基-3，5，5-三甲基环己烷酮的还原性胺化作用制备该化合物(流程24)。质谱(EI)显示母体离子m/e为167。 This compound was prepared by reductive amination of 3-cyano-3,5,5-trimethylcyclohexanone following the standard reductive amination procedure described above (Scheme 24). Mass spectrum (EI) showed a parent ion m/e of 167.
3-氨基-5-苯基噻喃(107)3-Amino-5-phenylthiopyran (107)
如流程25所示制备该化合物。因而，向0.96g(5mmol)5-苯基-3-噻喃酮(P.T.Lansbury等《美国化学会志》1970，92，5649)的50ml无水甲醇溶液中加入7.7g(100mmol)乙酸铵和6.5g 3A分子筛。在室温下搅拌30分钟后，分批加入1.25g(20mmol)氰基硼氢化钠。搅拌16小时后，对混合物进行重力过滤，在真空下蒸发甲醇。使残余物在冰/HCl与乙醚之间分配。将酸性含水相再用乙醚萃取两次，然后用冰和50％NaOH水溶液调至碱性。将混合物用CH2Cl2萃取，干燥(MgSO4)，蒸发，得到0.19g(20％)标题化合物。GC/MS显示纯度为100％，分子离子为193。
4-(4-三氟甲基)苯氧基环己胺(109)4-(4-Trifluoromethyl)phenoxycyclohexylamine (109)
按照流程26制备该化合物。历时10分钟向搅拌着的氢化钠(1.2g，0.05mol)的50ml DMF溶液中滴加1，4-二氧杂螺[4.5]癸烷-8-醇(7.5g，0.047mol)的15ml DMF溶液。将混合物在环境温度下搅拌30分钟。一齐加入4-氟三氟甲苯(7.71g，0.047mol)，将反应物在室温下搅拌2小时，然后在70℃下搅拌过夜。将反应混合物倒在冷水(700ml)中，加入1N HCl使溶液呈弱酸性。将混合物过滤，含水滤液用己烷萃取(2×150ml)。将滤出的固体溶于己烷萃取液，用水(50ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩，得到白色固体。该固体从甲醇/水中重结晶，得到纯的缩酮(8.6g，61％)。This compound was prepared according to Scheme 26. To a stirred solution of sodium hydride (1.2 g, 0.05 mol) in 50 ml DMF was added dropwise 1,4-dioxaspiro[4.5]decan-8-ol (7.5 g, 0.047 mol) in 15 ml DMF over 10 minutes solution. The mixture was stirred at ambient temperature for 30 minutes. 4-Fluorobenzotrifluoride (7.71 g, 0.047 mol) was added all at once, and the reaction was stirred at room temperature for 2 hours, then at 70°C overnight. The reaction mixture was poured into cold water (700ml), and 1N HCl was added to make the solution weakly acidic. The mixture was filtered and the aqueous filtrate was extracted with hexane (2 x 150ml). The filtered solid was dissolved in the hexane extract and washed with water (50ml). The solution was dried over MgSO4 , filtered and concentrated to give a white solid. The solid was recrystallized from methanol/water to give pure ketal (8.6 g, 61%).
将硅胶(30g)悬浮在150ml CH2Cl2中。历时5分钟向该悬液中滴加7ml 12％ HCl的水溶液。剧烈搅拌混合物，以防止凝集。加入上述缩酮(8.0g，26.49mmol)的75ml CH2Cl2溶液，将反应物搅拌3小时。然后将混合物过滤，硅胶垫用500ml CH2Cl2洗涤。蒸发溶剂，得到5.8g(86％)4-(4-三氟苯氧基)环己烷酮(108)。Silica gel (30 g) was suspended in 150 ml CH2Cl2 . To this suspension was added dropwise 7 ml of 12% HCl in water over 5 minutes. Stir the mixture vigorously to prevent clumping. A solution of the above ketal (8.0 g, 26.49 mmol ) in 75 mL CH2Cl2 was added and the reaction was stirred for 3 hours. The mixture was then filtered and the silica gel pad was washed with 500 ml CH2Cl2 . Evaporation of the solvent gave 5.8 g (86%) of 4-(4-trifluorophenoxy)cyclohexanone (108).
按照上述标准的还原性胺化操作进行酮108的还原性胺化，得到标题化合物109。 Reductive amination of ketone 108 was carried out following the standard reductive amination procedure described above to afford the title compound 109.
4-苯甲酰氧基-3，3，5，5-四甲基环己胺(111)4-Benzoyloxy-3,3,5,5-tetramethylcyclohexylamine (111)
按照流程27的操作制备该化合物。向冷却至0℃的搅拌着的7，7，9，9-四甲基-1，4-二氧杂螺[4.5]癸烷-8-醇(0.37g，1.73mmol)的6ml THF溶液中滴加n-BuLi(2.5M己烷溶液，1.73mmol，0.7ml)。将反应物搅拌10分钟。然后加入苯甲酰氯(1.73mmol，0.2ml)，使反应物温热至室温，搅拌过夜。将反应混合物倒在50ml 0.5N NaOH中，用乙醚萃取(3×20ml)。将醚层经MgSO4干燥，过滤，浓缩。残余物经过径向色谱纯化，用4∶1己烷-EtOAc作为洗脱剂。因而得到0.55g(～100％)苯甲酰氧基缩酮。This compound was prepared following the procedure in Scheme 27. To a stirred solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro[4.5]decane-8-ol (0.37g, 1.73mmol) in 6ml of THF cooled to 0°C n-BuLi (2.5M in hexane, 1.73mmol, 0.7ml) was added dropwise. The reaction was stirred for 10 minutes. Benzoyl chloride (1.73mmol, 0.2ml) was then added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 50ml 0.5N NaOH and extracted with ether (3 x 20ml). The ether layer was dried over MgSO4 , filtered and concentrated. The residue was purified by radial chromatography using 4:1 hexane-EtOAc as eluent. Thus 0.55 g (-100%) of the benzoyloxy ketal was obtained.
将硅胶(2.2g)悬浮在10ml CH2Cl2中。历时5分钟向该悬液中滴加0.5ml 12％ HCl的水溶液。剧烈搅拌混合物，以防止凝集。加入上述苯甲酰氧基缩酮的5ml CH2Cl2溶液，将反应物搅拌3小时。然后将混合物过滤，硅胶垫用100ml CH2Cl2洗涤。蒸发溶剂，得到0.46g(90％)苯甲酰氧基环己烷酮110，为澄清的油。Silica gel (2.2 g) was suspended in 10 ml CH2Cl2 . To this suspension was added dropwise 0.5 ml of 12% HCl in water over 5 minutes. Stir the mixture vigorously to prevent clumping. A solution of the above benzoyloxy ketal in 5 mL CH2Cl2 was added and the reaction was stirred for 3 hours. The mixture was then filtered and the silica gel pad was washed with 100 ml CH2Cl2 . Evaporation of the solvent gave 0.46 g (90%) of benzoyloxycyclohexanone 110 as a clear oil.
向搅拌着的苯甲酰氧基环己烷酮110(0.46g，1.68mmol)的4ml甲醇溶液中一齐加入盐酸羟胺(0.23g，3.25mmol)与乙酸钾(0.32g，3.25mmol)的4ml水溶液。将反应物在室温下搅拌过夜。加入水(20ml)，所得混合物用乙醚萃取(3×10ml)。将乙醚萃取液合并，用饱和NaHCO3(1×20ml)和盐水(1×15ml)洗涤。将醚层经MgSO4干燥，过滤，浓缩，得到所需的肟(0.39g，80％)，为E与Z异构体的混合物。Add hydroxylamine hydrochloride (0.23g, 3.25mmol) and potassium acetate (0.32g, 3.25mmol) in 4ml of aqueous solution to the stirred benzoyloxycyclohexane ketone 110 (0.46g, 1.68mmol) in 4ml of methanol solution . The reaction was stirred overnight at room temperature. Water (20ml) was added and the resulting mixture was extracted with ether (3 x 10ml). The ether extracts were combined, washed with saturated NaHCO 3 (1×20 ml) and brine (1×15 ml). The ether layer was dried over MgSO4 , filtered and concentrated to afford the desired oxime (0.39 g, 80%) as a mixture of E and Z isomers.
在500ml Parr压力瓶内，将Raney镍(湿重0.8g，AldrichChemical Co.)用水洗涤(3×20ml)，然后用乙醇洗涤(3×20ml)，每次滗析洗涤溶剂。向该洗涤后的催化剂加入肟(0.39g，1.35mmol)的无水乙醇(30ml)溶液。溶解需要该溶液的一些热量。向溶液中通入氨气1分钟，用氨饱和所得混合物。将该溶液置于Parr摇动器上，在氢气氛下(最初氢压＝50psig)摇动7小时。然后将反应混合物通过C盐垫过滤，蒸发溶剂，得到几乎无色的液体(0.37g，定量收率)。质子NMR和GC/MS与标题胺111的非对映体混合物(4∶1)是一致的。该物质无需另外纯化即可使用。 In a 500 ml Parr pressure bottle, Raney® nickel (0.8 g wet weight, Aldrich Chemical Co.) was washed with water (3 x 20 ml) and then with ethanol (3 x 20 ml), decanting the wash solvent each time. To the washed catalyst was added a solution of oxime (0.39 g, 1.35 mmol) in absolute ethanol (30 ml). Some heat of the solution is required for dissolution. Ammonia gas was bubbled through the solution for 1 minute to saturate the resulting mixture with ammonia. The solution was placed on a Parr shaker and shaken under a hydrogen atmosphere (initial hydrogen pressure = 50 psig) for 7 hours. The reaction mixture was then filtered through a pad of Celite® and the solvent was evaporated to give an almost colorless liquid (0.37 g, quantitative yield). Proton NMR and GC/MS were consistent with a diastereomeric mixture (4:1) of the title amine 111. This material was used without further purification.
4-氨基-2，2，6，6-四甲基环己基-6-氯-2-吡啶羧酸酯(113)4-amino-2,2,6,6-tetramethylcyclohexyl-6-chloro-2-pyridinecarboxylate (113)
如流程28所示合成该化合物。向冷却至0℃的搅拌着的7，7，9，9-四甲基-1，4-二氧杂螺[4.5]癸烷-8-醇(0.32g，1.50mmol)的5mlTHF溶液中滴加n-BuLi(2.5M己烷溶液，1.50mmol，0.6ml)。将反应物搅拌10分钟。然后加入6-氯吡啶甲酰氯(1.50mmol，0.26g)的1ml THF溶液，然后使反应物温热至室温。溶液固化，因此加入另外5ml THF，将反应物搅拌过夜。将反应混合物倒在40ml 0.5N NaOH中，用乙醚萃取(3×20ml)。将醚层经MgSO4干燥，过滤，浓缩。质子NMR揭示预期产物以及原料的比例为1.6∶1。这些化合物不能经过硅胶色谱分离，因此将该混合物用于下面的步骤并在那里纯化。This compound was synthesized as shown in Scheme 28. Drop into a solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro[4.5]decane-8-ol (0.32g, 1.50mmol) in 5ml THF which was cooled to 0°C Add n-BuLi (2.5M in hexane, 1.50mmol, 0.6ml). The reaction was stirred for 10 minutes. A solution of 6-chloropicolinate chloride (1.50 mmol, 0.26 g) in 1 ml THF was then added and the reaction was allowed to warm to room temperature. The solution solidified so another 5 ml THF was added and the reaction was stirred overnight. The reaction mixture was poured into 40ml 0.5N NaOH and extracted with ether (3 x 20ml). The ether layer was dried over MgSO4 , filtered and concentrated. Proton NMR revealed a 1.6:1 ratio of expected product to starting material. These compounds could not be chromatographed on silica gel, so the mixture was used in the next step and purified there.
将硅胶(1.4g)悬浮在10ml CH2Cl2中。历时5分钟向该悬液中滴加0.3ml 12％ HCl的水溶液。剧烈搅拌混合物，以防止凝集。加入上述混合物的5ml CH2Cl2溶液，将反应物搅拌3小时。然后将混合物过滤，硅胶垫用100ml CH2Cl2洗涤。蒸发溶剂，得到一种油。加入10ml 4∶1己烷-EtOAc溶液，进行所需吡啶甲酸酯112的沉淀。将所得固体过滤，用10ml 4∶1己烷-EtOAc洗涤。合并己烷-EtOAc洗液，蒸发，得到一种油。上述操作重复3次，得到吡啶甲酸酯112，为白色固体(214mg，两步收率46％)。质子NMR和GC/MS显示所需产物的纯度＞95％。Silica gel (1.4 g) was suspended in 10 ml CH2Cl2 . To this suspension was added dropwise 0.3 ml of 12% HCl in water over 5 minutes. Stir the mixture vigorously to prevent clumping. A solution of the above mixture in 5 ml CH2Cl2 was added and the reaction was stirred for 3 hours. The mixture was then filtered and the silica gel pad was washed with 100 ml CH2Cl2 . Evaporation of the solvent gave an oil. Precipitation of the desired picolinate 112 was effected by adding 10 mL of a 4:1 hexane-EtOAc solution. The resulting solid was filtered and washed with 10 mL of 4:1 hexane-EtOAc. The combined hexane-EtOAc washes were evaporated to an oil. The above operation was repeated 3 times to obtain picolinate 112 as a white solid (214 mg, 46% yield in two steps). Proton NMR and GC/MS showed >95% purity of the desired product.
将该酯(200mg，0.65mmol)、异丙醇钛(IV)(1.30mmol，0.38ml)、氯化铵(1.30mmol，70mg)与三乙胺(1.30mmol，0.18ml)在绝对乙醇(10ml)中的混合物在室温氮下搅拌12小时。然后加入硼氢化钠(0.97mmol，40mg)，将所得化合物在环境温度下搅拌另外8小时。然后将反应物倒在氨水(20ml，2.0M)中猝灭反应，所得溶液用乙醚萃取(3×20ml)。将合并后的乙醚萃取液用2N HCl萃取(2×20ml)，以分离非碱性物质。将酸性溶液用乙醚(20ml)洗涤一次，然后用含水氢氧化钠(2N)处理至pH 10-12，用EtOAc萃取(3×20ml)。将合并后的EtOAc洗液经MgSO4干燥，过滤，浓缩，得到一种油。该物质与标题环己胺的6∶1非对映体混合物是一致的。质子NMR和GC/MS显示所需产物的纯度为～75％。该胺混合物无需进一步纯化即可使用。The ester (200mg, 0.65mmol), titanium (IV) isopropoxide (1.30mmol, 0.38ml), ammonium chloride (1.30mmol, 70mg) and triethylamine (1.30mmol, 0.18ml) in absolute ethanol (10ml ) was stirred at room temperature under nitrogen for 12 hours. Sodium borohydride (0.97 mmol, 40 mg) was then added and the resulting compound was stirred at ambient temperature for a further 8 hours. The reaction was then quenched by pouring into aqueous ammonia (20ml, 2.0M), and the resulting solution was extracted with ether (3 x 20ml). The combined ether extracts were extracted with 2N HCl (2 x 20 mL) to separate the non-basic material. The acidic solution was washed once with diethyl ether (20ml), then treated with aqueous sodium hydroxide (2N) to pH 10-12 and extracted with EtOAc (3 x 20ml). The combined EtOAc washes were dried over MgSO4 , filtered and concentrated to an oil. This material was identical to a 6:1 diastereomeric mixture of the title cyclohexylamine. Proton NMR and GC/MS showed the desired product to be -75% pure. The amine mixture was used without further purification.
反式-2-甲硫基环己胺
利用B.M.Trost和T.Shibata《美国化学会志》1982，104，3225的氮杂亚磺酰化技术从环己烯制备该胺。4-苯硫基环己胺(115)The amine was prepared from cyclohexene using the azasulfnylation technique of BMTrost and T. Shibata J. Am. Chem. 1982, 104, 3225. 4-Phenylthiocyclohexylamine (115)
按照流程29所示操作制备该化合物。向搅拌着的4-苯硫基环己烷酮(V.K.Yadav和D.A.Jeyaraj《有机化学杂志》1998，63，3474)(1.20g，5.83mmol)的20ml甲醇溶液中一齐加入盐酸苄氧基胺(1.80g，11.22mmol)与乙酸钾(1.10g，11.22mmol)的20ml水溶液。将反应物在室温下搅拌过夜。加入水(60ml)，所得混合物用乙醚萃取(3×40ml)。将乙醚萃取液合并，用饱和NaHCO3(1×50ml)和盐水(1×40ml)洗涤。将醚层经MgSO4干燥，过滤，浓缩，得到一种油。该物质经由径向色谱纯化(9∶1己烷-EtOAc)，得到相应的O-苄基肟114(1.72g，95％)，为E与Z异构体的混合物。This compound was prepared following the procedure shown in Scheme 29. Add benzyloxyamine hydrochloride (1.80g , 11.22mmol) and potassium acetate (1.10g, 11.22mmol) in 20ml aqueous solution. The reaction was stirred overnight at room temperature. Water (60ml) was added and the resulting mixture was extracted with ether (3 x 40ml). The ether extracts were combined, washed with saturated NaHCO 3 (1×50 ml) and brine (1×40 ml). The ether layer was dried over MgSO4 , filtered and concentrated to an oil. This material was purified via radial chromatography (9:1 hexanes-EtOAc) to afford the corresponding O-benzyl oxime 114 (1.72 g, 95%) as a mixture of E and Z isomers.
将氢化锂铝(5.08mmol，0.19g)悬浮在10ml无水乙醚中，冷却至0℃。滴加O-苄基肟114的5ml乙醚溶液，使反应物温热至室温，搅拌4小时。同时小心地加入水(0.2ml)和1N NaOH(0.2ml)以破坏过量氢化锂铝。将混合物过滤，盐用50ml乙醚洗涤。蒸发溶剂，得到0.62g(93％)标题胺115，为一种油。质子NMR和GC/MS揭示产物是1.3∶1的非对映胺，纯度＞95％。
3-{[3-(三氟甲基)-2-吡啶基]硫基}环己胺(117)3-{[3-(trifluoromethyl)-2-pyridyl]sulfanyl}cyclohexylamine (117)
按照流程30所示方法制备该胺。在环境温度下，向搅拌着的2-环己烯-1-酮(0.44ml，4.58mmol)与2-巯基-5-三氟甲基吡啶(0.82g，4.58mmol)的20ml CH2Cl2溶液中加入三氯化铋(60mg，0.18mmol)。将反应物在室温下搅拌过夜，浓缩。残余物经由径向色谱纯化，用4∶1己烷-EtOAc作为洗脱剂，得到1.12g(89％)共轭加成产物2-(3-氧代环己硫基)-5-三氟甲基吡啶(116)。The amine was prepared as shown in Scheme 30. To stirred 2-cyclohexen-1-one (0.44ml, 4.58mmol) and 2-mercapto-5-trifluoromethylpyridine (0.82g, 4.58mmol) in 20ml CH2Cl2 Bismuth trichloride (60 mg, 0.18 mmol) was added to the solution. The reaction was stirred overnight at room temperature and concentrated. The residue was purified via radial chromatography using 4:1 hexane-EtOAc as eluent to afford 1.12 g (89%) of the conjugated addition product 2-(3-oxocyclohexylthio)-5-trifluoro Picoline (116).
向搅拌着的116(0.26g，0.95mmol)的3ml甲醇溶液中一齐加入盐酸苄氧基胺(0.29g，1.83mmol)与乙酸钾(0.18g，1.83mmol)的3ml水溶液。将反应物在室温下搅拌过夜。加入水(10ml)，所得混合物用乙醚萃取(3×10ml)。将乙醚萃取液合并，用饱和NaHCO3(1×15ml)和盐水(1×15ml)洗涤。将醚层经MgSO4干燥，过滤，浓缩，得到一种油。该物质经由径向色谱纯化(9∶1己烷-EtOAc)，得到分离的肟(0.32g，89％)。E-异构体(Rf＝0.33)和Z-异构体(Rf＝0.25)显示一致的质子NMR和GC/MS光谱特征。To a stirred solution of 116 (0.26g, 0.95mmol) in 3ml of methanol was added benzyloxyamine hydrochloride (0.29g, 1.83mmol) and potassium acetate (0.18g, 1.83mmol) in 3ml of aqueous solution all at once. The reaction was stirred overnight at room temperature. Water (10ml) was added and the resulting mixture was extracted with ether (3 x 10ml). The ether extracts were combined, washed with saturated NaHCO 3 (1×15 ml) and brine (1×15 ml). The ether layer was dried over MgSO4 , filtered and concentrated to an oil. This material was purified via radial chromatography (9:1 hexanes-EtOAc) to afford the isolated oxime (0.32 g, 89%). The E-isomer ( Rf = 0.33) and the Z-isomer ( Rf = 0.25) showed consistent proton NMR and GC/MS spectral characteristics.
将氢化锂铝(1.33mmol，50mg)悬浮在3ml无水乙醚中，冷却至0℃。滴加混合肟的1ml乙醚溶液，使反应物温热至室温，搅拌4小时。同时小心地加入水(50μl)和1N NaOH(50μl)以破坏过量氢化锂铝。将混合物过滤，盐用乙醚洗至体积为100ml。乙醚溶液用2N HCl萃取(2×50ml)，以分离非碱性物质。将酸性水溶液用乙醚(50ml)洗涤一次，然后用含水氢氧化钠(2M)处理至pH 10-12，用乙醚萃取(3×50ml)。将醚层经MgSO4干燥，过滤，浓缩，得到121mg(52％)所需的标题胺117，为一种油。质子NMR和GC/MS揭示产物是1.3∶1的非对映胺，纯度＞95％。
1-(5-氨基-1，3，3-三甲基环己基)-4-苯基-1-丁烷酮(120)1-(5-Amino-1,3,3-trimethylcyclohexyl)-4-phenyl-1-butanone (120)
通过流程31所述方法实现该胺的合成。将室温下的萘(1.23g，9.57mmol)与锂颗粒(67mg，9.57mmol)的10ml THF悬液在氮下搅拌过夜。将该萘基锂溶液冷却至-60℃，加入苯基3-苯丙基硫(1.1g，4.78mmol)。将反应物冷却至-20℃，以确保反应完全，然后重新冷却至-60℃。加入7-氰基-7，9，9-三甲基-1，4-二氧杂螺[4.5]癸烷(0.5g，2.39mmol)的5ml THF溶液，使溶液温热至0℃，在该温度下搅拌2小时。加入10ml饱和氯化铵溶液猝灭反应，然后用2N HCl处理至pH～4，在室温下搅拌过夜。将混合物用乙醚萃取(3×30ml)，经MgSO4干燥，过滤，蒸发。残余物经由径向色谱纯化，用6∶1己烷-EtOAc作为洗脱剂。因而得到3-(2-氧代-4-苯基丁基)-3，5，5-三甲基环己烷酮118(136mg，Rf＝0.18)及其缩酮(509mg，Rf＝0.33)的1∶3混合物，后者是不完全水解的产物。计算1-锂-3-苯基丙烷向腈加成的总收率为85％。Synthesis of this amine was achieved by the method described in Scheme 31. A room temperature suspension of naphthalene (1.23 g, 9.57 mmol) and lithium particles (67 mg, 9.57 mmol) in 10 ml THF was stirred under nitrogen overnight. The naphthyllithium solution was cooled to -60°C, and phenyl 3-phenylpropylsulfide (1.1 g, 4.78 mmol) was added. The reaction was cooled to -20°C to ensure completion of the reaction, then re-cooled to -60°C. Add 7-cyano-7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane (0.5g, 2.39mmol) in 5ml THF solution, warm the solution to 0°C, and Stirring was carried out at this temperature for 2 hours. The reaction was quenched by adding 10 ml of saturated ammonium chloride solution, then treated with 2N HCl to pH~4, and stirred overnight at room temperature. The mixture was extracted with ether (3x30ml), dried over MgSO4 , filtered and evaporated. The residue was purified via radial chromatography using 6:1 hexane-EtOAc as eluent. Thus 3-(2-oxo-4-phenylbutyl)-3,5,5-trimethylcyclohexanone 118 (136 mg, R f =0.18) and its ketal (509 mg, R f = 0.33), the latter being the product of incomplete hydrolysis. The overall yield of addition of 1-lithium-3-phenylpropane to the nitrile was calculated to be 85%.
将硅胶(1.82g)悬浮在10ml CH2Cl2中。历时5分钟向该悬液中滴加0.41ml 12％ HCl的水溶液。剧烈搅拌混合物，以防止凝集。加入上述缩酮的2ml CH2Cl2溶液，将反应物搅拌3小时。然后将混合物过滤，硅胶垫用50ml CH2Cl2洗涤。蒸发溶剂，得到0.48g(100％)3-(1-氧代-4-苯基丁基)-3，5，5-三甲基环己烷酮(118)，为澄清的油，与其NMR和GC/MS性质是一致的。Silica gel (1.82 g) was suspended in 10 ml CH2Cl2 . To this suspension was added dropwise 0.41 ml of 12% HCl in water over 5 minutes. Stir the mixture vigorously to prevent clumping. A solution of the above ketal in 2 ml CH2Cl2 was added and the reaction was stirred for 3 hours. The mixture was then filtered and the silica gel pad was washed with 50 ml CH2Cl2 . Evaporation of the solvent gave 0.48 g (100%) of 3-(1-oxo-4-phenylbutyl)-3,5,5-trimethylcyclohexanone (118) as a clear oil, and its NMR Consistent with GC/MS properties.
向搅拌着的该双-酮(0.62g，2.17mmol)的7ml甲醇溶液中一齐加入盐酸羟胺(0.16g，2.28mmol)与乙酸钾(0.25g，3.03mmol)的7ml水溶液。将反应物在室温下搅拌1小时。加入水(20ml)，所得混合物用乙醚萃取(3×20ml)。将乙醚萃取液合并，用饱和NaHCO3(1×20ml)和盐水(1×20ml)洗涤。将醚层经MgSO4干燥，过滤，浓缩，得到所需的单-肟119(0.57g，87％)，为E与Z异构体的混合物。To a stirred solution of the di-ketone (0.62 g, 2.17 mmol) in 7 ml of methanol was added all at once a 7 ml aqueous solution of hydroxylamine hydrochloride (0.16 g, 2.28 mmol) and potassium acetate (0.25 g, 3.03 mmol). The reaction was stirred at room temperature for 1 hour. Water (20ml) was added and the resulting mixture was extracted with ether (3 x 20ml). The ether extracts were combined, washed with saturated NaHCO 3 (1×20ml) and brine (1×20ml). The ether layer was dried over MgSO4 , filtered and concentrated to afford the desired mono-oxime 119 (0.57 g, 87%) as a mixture of E and Z isomers.
在500ml Parr压力瓶内，将Raney镍(湿重0.8g，AldrichChemical Co.)用水洗涤(3×20ml)，然后用乙醇洗涤(3×20ml)，每次滗析洗涤溶剂。向该洗涤后的催化剂加入肟119(0.57g，1.89mmol)的无水乙醇(40ml)溶液。向溶液中通入氨气1分钟，用氨饱和所得混合物。将该溶液置于Parr摇动器上，在氢气氛下(最初氢压＝50psig)摇动7小时。然后将反应混合物通过C盐垫过滤，蒸发溶剂，得到一种油(0.43g，80％)。GC/MS分析显示是标题胺120的1∶1非对映体混合物以及少量未被鉴别的副产物。该胺混合物无需进一步纯化即可直接使用。
2-苄基-6-甲基-4-吡喃基胺(122)2-Benzyl-6-methyl-4-pyranylamine (122)
按照流程32制备该胺。向0.37g(1.8mmol)2-苄基-6-甲基-4-吡喃酮(G.Piancatilli等《合成》1982，248)中加入0.22g(3.1mmol)盐酸羟胺与0.16g(2mmol)乙酸钾的10ml甲醇溶液。搅拌过夜后，使混合物在CH2Cl2与水之间分配。将有机相干燥并蒸发。油性残余物在室温下放置后固化，得到0.4g(99％)所需的肟121，GC/MS证实是1∶1Z/E异构体混合物，分子离子为219，直接用于下面的还原反应。The amine was prepared according to Scheme 32. Add 0.22 g (3.1 mmol) of hydroxylamine hydrochloride and 0.16 g (2 mmol) of 0.37 g (1.8 mmol) of 2-benzyl-6-methyl-4-pyrone (G.Piancatilli et al. Potassium acetate in 10 ml of methanol. After stirring overnight , the mixture was partitioned between CH2Cl2 and water. The organic phase was dried and evaporated. The oily residue solidified upon standing at room temperature to afford 0.4 g (99%) of the desired oxime 121, which was confirmed by GC/MS to be a 1:1 Z/E isomer mixture with molecular ion 219, which was used directly in the following reduction .
向0.4g 2-苄基-6-甲基-4-吡喃酮肟(121)(1.8mmol)的50ml95％乙醇溶液中加入0.8g(湿重)已经用水洗涤3次并用乙醇洗涤3次的Raney镍。将混合物置于Parr摇动器内41psig氢下达32小时。放空后，对混合物进行重力过滤，在真空下蒸发。使残余物在CH2Cl2与碳酸钠水溶液之间分配。将有机相干燥，在真空下蒸发，得到0.19g所需的标题胺122加肟121的混合物，GC/MS分析是2∶1混合物。混合物无需进一步分离即可使用。To 0.4 g of 2-benzyl-6-methyl-4-pyrone oxime (121) (1.8 mmol) in 50 ml of 95% ethanol solution, add 0.8 g (wet weight) of 3 times of water and 3 times of ethanol. Raney® Nickel . The mixture was placed in a Parr shaker under hydrogen at 41 psig for 32 hours. After venting, the mixture was gravity filtered and evaporated under vacuum. The residue was partitioned between CH2Cl2 and aqueous sodium carbonate. The organic phase was dried and evaporated in vacuo to give 0.19 g of the desired mixture of title amine 122 plus oxime 121, a 2:1 mixture by GC/MS analysis. The mixture was used without further separation.
1-苯甲酰基-4-氨基哌啶
1-(4-甲基苄基)-4-哌啶基胺(125)1-(4-Methylbenzyl)-4-piperidinylamine (125)
按照流程33实现该化合物的合成。向5.05g(50mmol)4-羟基哌啶与7.08g(50mmol)对-甲基苄基氯的25ml叔丁醇溶液重加入过量固体碳酸钾，将混合物在蒸汽浴上加热3小时。将混合物冷却至室温，使其在乙醚与水之间分配。有机相用冷的稀HCl萃取，酸性含水相用乙醚萃取两次。用冰与50％含水NaOH使含水相呈碱性，用乙醚萃取。将乙醚相用稀碳酸氢钠水溶液、盐水洗涤，干燥，在真空下蒸发，得到5.3g(52％)1-(4-甲基苄基)-4-羟基哌啶(123)，为一种油。GC/MS显示纯度为100％，分子离子为205。Synthesis of this compound was achieved following Scheme 33. To a solution of 5.05 g (50 mmol) 4-hydroxypiperidine and 7.08 g (50 mmol) p-methylbenzyl chloride in 25 ml tert-butanol was added excess solid potassium carbonate and the mixture was heated on a steam bath for 3 hours. The mixture was cooled to room temperature and partitioned between ether and water. The organic phase was extracted with cold dilute HCl and the acidic aqueous phase was extracted twice with diethyl ether. The aqueous phase was made basic with ice and 50% aqueous NaOH and extracted with ether. The ether phase was washed with dilute aqueous sodium bicarbonate, brine, dried and evaporated in vacuo to yield 5.3 g (52%) of 1-(4-methylbenzyl)-4-hydroxypiperidine (123) as a Oil. GC/MS showed 100% purity with 205 molecular ion.
向-78℃下的2.8ml(32mmol)草酰氯的75ml CH2Cl2溶液中加入4.6ml(64mmol)DMSO。向该混合物中加入5.3g(26mmol)1-(4-甲基苄基)-4-哌啶醇(123)的10ml CH2Cl2溶液，将混合物在冷却下搅拌5分钟。用18ml(129mmol)三乙胺猝灭混合物，使其达到室温，加入饱和含水氯化铵。将有机相用水和盐水洗涤，干燥，蒸发，得到4.27g(81％)1-(4-甲基苄基)-4-哌啶酮(124)，无需进一步纯化即可使用。GC/MS显示纯度为100％，分子离子为203。To a solution of 2.8 ml (32 mmol) oxalyl chloride in 75 ml CH2Cl2 at -78°C was added 4.6 ml (64 mmol) DMSO. To this mixture was added a solution of 5.3 g (26 mmol) of 1-(4-methylbenzyl)-4-piperidinol (123) in 10 ml of CH2Cl2 , and the mixture was stirred under cooling for 5 minutes. The mixture was quenched with 18 ml (129 mmol) triethylamine, allowed to come to room temperature, and saturated aqueous ammonium chloride was added. The organic phase was washed with water and brine, dried and evaporated to give 4.27 g (81%) of 1-(4-methylbenzyl)-4-piperidone (124), which was used without further purification. GC/MS showed 100% purity with molecular ion 203.
向4.25g(21mmol) 1-(4-甲基苄基)-4-哌啶酮124的200ml无水甲醇溶液中加入32.2g(420mmol)乙酸铵和25g 3A分子筛。搅拌10分钟后，分批加入5.25g(84mmol)氰基硼氢化钠。搅拌16小时后，对混合物进行重力过滤，在真空下蒸发甲醇。使残余物在乙醚与冰/HCl之间分配。将酸性含水层用乙醚萃取两次，用50％含水NaOH与冰调至碱性，用CH2Cl2萃取，得到2.1g(48％)标题胺125，为浓稠的油。GC/MS显示分子离子为204。产物无需进一步纯化即可使用。 To a solution of 4.25 g (21 mmol) of 1-(4-methylbenzyl)-4-piperidone 124 in 200 ml of dry methanol was added 32.2 g (420 mmol) of ammonium acetate and 25 g of 3A molecular sieves. After stirring for 10 minutes, 5.25 g (84 mmol) of sodium cyanoborohydride were added in portions. After stirring for 16 hours, the mixture was gravity filtered and the methanol was evaporated under vacuum. The residue was partitioned between ether and ice/HCl. The acidic aqueous layer was extracted twice with ether , made basic with 50% aqueous NaOH and ice, and extracted with CH2Cl2 to afford 2.1 g (48%) of the title amine 125 as a thick oil. GC/MS showed molecular ion 204. The product was used without further purification.
1-(3-三氟甲基苄基)-4-哌啶基胺(127)1-(3-Trifluoromethylbenzyl)-4-piperidinylamine (127)
按照流程34制备。向0.8g(3.1mmol)1-(3-三氟甲基苄基)-4-哌啶酮(按照与1-(4-甲基苄基)-4-哌啶酮123相同方式制备)的7ml吡啶溶液中加入0.22g(3.1mmol)盐酸羟胺，将混合物搅拌过夜。在真空下蒸发混合物，使残余物在乙醚与稀含水碳酸氢钠之间分配。将有机相干燥，在真空下蒸发，得到0.52g(62％)肟，为一种油，直接用于下面的氢化步骤。GC/MS显示分子离子为272。Prepared according to Scheme 34. To 0.8g (3.1mmol) of 1-(3-trifluoromethylbenzyl)-4-piperidone (prepared in the same manner as 1-(4-methylbenzyl)-4-piperidone 123) 0.22 g (3.1 mmol) of hydroxylamine hydrochloride was added to 7 ml of pyridine solution, and the mixture was stirred overnight. The mixture was evaporated under vacuum and the residue was partitioned between diethyl ether and dilute aqueous sodium bicarbonate. The organic phase was dried and evaporated under vacuum to yield 0.52 g (62%) of the oxime as an oil which was used directly in the next hydrogenation step. GC/MS showed molecular ion 272.
向0.5g(2mmol)该肟的75ml乙醇溶液中加入0.5g(湿重)已经用水洗涤3次并用乙醇洗涤3次的Raney镍。向混合物中通入氨气达若干分钟，将混合物置于Parr摇动器内45psig氢下达7小时。放空容器，对混合物进行重力过滤。将残余物溶于乙醚，过滤，蒸发，得到0.43g(81％)标题胺127，无需进一步纯化即可使用。GC/MS显示为单一的峰，分子离子为258。 To a solution of 0.5 g (2 mmol) of this oxime in 75 ml ethanol was added 0.5 g (wet weight) of Raney® nickel which had been washed 3 times with water and 3 times with ethanol. Ammonia gas was bubbled through the mixture for several minutes and the mixture was placed in a Parr shaker under hydrogen at 45 psig for 7 hours. The container was emptied and the mixture was gravity filtered. The residue was dissolved in ether, filtered and evaporated to give 0.43 g (81%) of the title amine 127 which was used without further purification. GC/MS showed a single peak with molecular ion 258.
顺式/反式-2-甲基-3-四氢呋喃基胺(128)cis/trans-2-methyl-3-tetrahydrofurylamine (128)
按照流程35的方法得到该胺。向1.15g(10mmol)2-甲基四氢呋喃-3-酮肟(从商业上可得到的2-甲基四氢呋喃-3-酮经由标准操作制备)的50ml甲醇溶液中加入1g(湿重)已经各用水和乙醇洗涤3次的Raney镍，置于Parr摇动器内44psig氢下。18小时后，放空混合物，进行重力过滤。在真空下蒸发甲醇，将残余物溶于乙醚，干燥。在真空下蒸发醚相，得到0.6g(59％)标题胺128，为顺式/反式混合物。GC/MS显示41％的分子离子为101，59％的分子离子为101。胺混合物无需进一步纯化即可使用。 The amine was obtained following the procedure in Scheme 35. To a solution of 1.15 g (10 mmol) of 2-methyltetrahydrofuran-3-one oxime (prepared from commercially available 2-methyltetrahydrofuran-3-one via standard procedures) in 50 ml of methanol was added 1 g (wet weight) of each Raney (R) nickel washed 3 times with water and ethanol and placed under 44 psig hydrogen in a Parr shaker. After 18 hours, the mixture was vented and gravity filtered. Methanol was evaporated under vacuum and the residue was dissolved in ether and dried. Evaporation of the ether phase under vacuum gave 0.6 g (59%) of the title amine 128 as a cis/trans mixture. GC/MS showed 41% of the molecular ion to be 101 and 59% to be 101. The amine mixture was used without further purification.
2-苄基-2，6-二甲基-4-吡喃基胺(133)2-Benzyl-2,6-dimethyl-4-pyranylamine (133)
按照流程36所述操作得到该胺。向-78℃下的4.88g(19.7mmol)3-三甲基甲硅烷氧基丁酸三甲基甲硅烷基酯的40ml CH2Cl2溶液中加入2.4g(18mmol)甲基苄基酮和1滴三甲基甲硅烷基三氟甲磺酸酯。使混合物在冷却下放置2天，然后用0.5ml吡啶猝灭，使其达到室温。将有机相用稀碳酸氢钠水溶液洗涤，干燥，在真空下蒸发。在真空下蒸馏残余物，得到2.89g(67％)2-苄基-2，6-二甲基-4-亚甲基-1，3-二噁烷-4-酮(129)，0.6mm下的b.p.125-32℃。GC/MS显示是两种异构体，各自的基本峰为134(甲基苄基酮)。The amine was obtained by working up as described in Scheme 36. To a solution of 4.88 g (19.7 mmol) of trimethylsilyl 3 -trimethylsiloxybutyrate in 40 ml of CH Cl at -78°C was added 2.4 g (18 mmol) of methylbenzyl ketone and 1 drop of trimethylsilyl triflate. The mixture was left under cooling for 2 days, then quenched with 0.5 ml pyridine and allowed to come to room temperature. The organic phase was washed with dilute aqueous sodium bicarbonate, dried and evaporated under vacuum. The residue was distilled under vacuum to give 2.89 g (67%) of 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxan-4-one (129), 0.6 mm under bp125-32°C. GC/MS showed two isomers with each base peak at 134 (methyl benzyl ketone).
向氮下的1.5g(6.8mmol)2-苄基-2，6-二甲基-4-亚甲基-1，3-二噁烷-4-酮(129)中加入2.9g(13.9mmol)双-(环戊基)-双-甲基环戊二烯钛的20ml无水THF溶液。将混合物在回流下加热16小时。将反应混合物冷却至室温，用过量乙醚猝灭。将全部混合物通过硅胶床过滤，用乙醚作为洗脱剂。蒸发滤液，经过硅胶色谱纯化，用含有0.2％三乙胺的EtOAc与己烷(1∶4)洗脱。蒸发含有产物的部分，悬浮在石油醚中，在真空下过滤，得到1.2g固体。GC/MS显示是分子离子为218的2-苄基-2，6-二甲基-4-亚甲基-1，3-二噁烷(130)与原料129的大约3∶1混合物。混合物直接用于下面的重排作用。To 1.5 g (6.8 mmol) of 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxan-4-one (129) under nitrogen was added 2.9 g (13.9 mmol ) Bis-(cyclopentyl)-bis-methylcyclopentadienyl titanium in 20 ml of anhydrous THF. The mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and quenched with excess ether. The whole mixture was filtered through a bed of silica gel using diethyl ether as eluent. The filtrate was evaporated and purified by silica gel chromatography, eluting with EtOAc and hexanes (1:4) containing 0.2% triethylamine. Fractions containing product were evaporated, suspended in petroleum ether and filtered under vacuum to give 1.2 g of a solid. GC/MS showed an approximately 3:1 mixture of 218 molecular ion 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxane (130) and starting material 129. The mixture was used directly in the rearrangement below.
在-78℃下，向氮下的1.2g(5.5mmol)该混合物的5ml甲苯溶液中加入10.99ml(11mmol)氢化三异丁基铝。使反应物在冷却下放置16小时，然后用几滴水猝灭。使混合物达到室温，加入过量饱和含水氯化铵。混合物用过量CH2Cl2萃取，难以分离铝盐。将有机层干燥，蒸发，得到1.1g(90％)2-苄基-2，6-二甲基-4-羟基吡喃醇(131)，为75∶2 5异构体混合物(GC/MS)。To a solution of 1.2 g (5.5 mmol) of this mixture in 5 ml of toluene under nitrogen was added 10.99 ml (11 mmol) of triisobutylaluminum hydride at -78°C. The reaction was left under cooling for 16 hours, then quenched with a few drops of water. The mixture was allowed to reach room temperature and excess saturated aqueous ammonium chloride was added. The mixture was extracted with excess CH2Cl2 and the aluminum salt was difficult to separate. The organic layer was dried and evaporated to yield 1.1 g (90%) of 2-benzyl-2,6-dimethyl-4-hydroxypyranol (131) as a 75:2 mixture of isomers (GC/MS ).
在磁搅拌下，向1.1g(5mmol)131的10ml CH2Cl2溶液中分批加入1.6g(7.5mmol)氯铬酸吡啶鎓。在室温下1小时后，加入乙醚，将混合物通过硅胶床过滤，用乙醚洗涤。蒸发滤液，得到0.88g(80％)2-苄基-2，6-二甲基-4-吡喃酮(132)。GC/MS显示纯度为99％，基本峰为127(M-苄基)。该异构体混合物直接用于下面的还原性胺化作用。To a solution of 1.1 g (5 mmol) 131 in 10 ml CH 2 Cl 2 was added portionwise 1.6 g (7.5 mmol) pyridinium chlorochromate under magnetic stirring. After 1 hour at room temperature, diethyl ether was added and the mixture was filtered through a bed of silica gel, washing with diethyl ether. Evaporation of the filtrate gave 0.88 g (80%) of 2-benzyl-2,6-dimethyl-4-pyrone (132). GC/MS showed a purity of 99% with a base peak of 127 (M-benzyl). This isomer mixture was used directly in the following reductive amination.
向0.88g(4mmol) 132的40ml无水甲醇溶液中加入6.16g(80mmol)乙酸铵和5g 3A分子筛。在室温下搅拌45分钟后，在磁搅拌下分批加入1.02g(16mmol)氰基硼氢化钠。对混合物进行重力过滤，在真空下蒸发甲醇。使残余物在乙醚与冷的稀HCl之间分配。含水相用乙醚萃取两次，然后用冰与50％含水NaOH调至碱性。将产物用CH2Cl2萃取，干燥，蒸发，得到0.43g(49％)标题胺133的两组分异构体混合物。GC/MS显示58％的分子离子为128，42％的分子离子为128。
1-(3-苯基丙酰基)-4-氨基哌啶(136)1-(3-Phenylpropionyl)-4-aminopiperidine (136)
按照流程37的方法合成该胺。向4g(40mmol)4-羟基哌啶的20ml甲苯溶液中加入苯基丙酰氯(在过量亚硫酰氯中从6g(40mmol)苯基丙酸得到)。向混合物中加入过量2N含水NaOH。搅拌24小时后，弃去甲苯层，将含水相用CH2Cl2萃取，干燥，在真空下蒸发，得到3.63g(39％)1-(3-苯基丙酰基)-4-羟基哌啶(134)。GC/MS显示纯度为100％，分子离子为233。The amine was synthesized according to the method of Scheme 37. To a solution of 4 g (40 mmol) 4-hydroxypiperidine in 20 ml toluene was added phenylpropionyl chloride (obtained from 6 g (40 mmol) phenylpropanoic acid in excess thionyl chloride). To the mixture was added excess 2N aqueous NaOH. After stirring for 24 hours, the toluene layer was discarded and the aqueous phase was extracted with CH2Cl2 , dried and evaporated in vacuo to yield 3.63 g (39%) of 1-(3-phenylpropionyl)-4-hydroxypiperidine (134). GC/MS showed 100% purity with molecular ion 233.
向-78℃下的1.68ml草酰氯(19.2mmol)的35ml CH2Cl2溶液中加入2.73ml(38.5mmol)无水DMSO的5ml CH2Cl2溶液。加入后，加入3.6g(15.4mmol)1-(3-苯基丙酰基)-4-羟基哌啶134的5ml CH2Cl2溶液，将混合物在冷却下搅拌5分钟。加入10.73ml(77mmol)三乙胺的5ml CH2Cl2溶液，使混合物达到室温。用饱和氯化铵水溶液猝灭混合物。将有机相用水洗涤两次，用饱和盐水洗涤，干燥，在真空下蒸发，得到3.2g(89％)1-(3-苯基丙酰基)-4-酮基哌啶(135)。GC/MS显示纯度为100％，分子离子为231。To a solution of 1.68 ml oxalyl chloride (19.2 mmol ) in 35 ml CH2Cl2 at -78°C was added 2.73 ml (38.5 mmol) of anhydrous DMSO in 5 ml CH2Cl2 . After the addition, a solution of 3.6 g (15.4 mmol) of 1-(3-phenylpropionyl)-4-hydroxypiperidine 134 in 5 ml of CH2Cl2 was added and the mixture was stirred for 5 minutes under cooling . A solution of 10.73 ml (77 mmol) triethylamine in 5 ml CH2Cl2 was added and the mixture was allowed to reach room temperature. The mixture was quenched with saturated aqueous ammonium chloride. The organic phase was washed twice with water, washed with saturated brine, dried and evaporated under vacuum to give 3.2 g (89%) of 1-(3-phenylpropanoyl)-4-ketopiperidine (135). GC/MS showed 100% purity with 231 molecular ion.
向3.2g(13.8mmol)135的125ml无水甲醇溶液中加入21.3g乙酸铵和20g 3A分子筛。搅拌30分钟后，在搅拌下分批加入3.47g(55.2mmol)氰基硼氢化钠。3小时后，对混合物进行重力过滤，在真空下蒸发甲醇。使残余物在冰/HCl与乙醚之间分配。酸性含水相再用乙醚萃取两次。用冰与50％含水NaOH使含水相呈碱性。将混合物用CH2Cl2萃取，干燥，在真空下蒸发，得到1.5g(47％)标题胺136。GC/MS显示纯度为100％，分子离子为232。
胺139的制备Preparation of amine 139
该胺的合成如流程38所示。在带有螺帽的聚四氟乙烯试管内装入137(M.Shimano等《四面体》1998，54，12745)(0.80g，1.21mmol)和6ml吡啶。将溶液冷却至0℃，用1.1ml HF-吡啶配合物处理，使溶液温热至室温，搅拌17小时。然后加入另外1.1ml HF-吡啶，将反应物搅拌另外30小时。将该混合物倒在搅拌着的40ml 1N HCl与20ml 1∶1己烷-二乙醚的冰冷溶液中。分离各层，含水层用1∶1己烷-二乙醚萃取(2×20ml)。将合并后的有机层用冰冷的1N HCl(1×20ml)和盐水(1×20ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。粗产物经由径向色谱纯化(3∶1己烷-EtOAc)，得到282mg羟基酯(加少量杂质)，直接进行下面的步骤。The synthesis of this amine is shown in Scheme 38. 137 (M. Shimano et al. "Tetrahedron" 1998, 54, 12745) (0.80 g, 1.21 mmol) and 6 ml of pyridine were charged into a Teflon test tube with a screw cap. The solution was cooled to 0°C, treated with 1.1 ml of HF-pyridine complex, allowed to warm to room temperature, and stirred for 17 hours. A further 1.1 ml of HF-pyridine was then added and the reaction was stirred for a further 30 hours. The mixture was poured into a stirred ice-cold solution of 40 mL 1N HCl and 20 mL 1:1 hexane-diethyl ether. The layers were separated and the aqueous layer was extracted with 1:1 hexane-diethyl ether (2 x 20ml). The combined organic layers were washed with ice-cold 1N HCl (1 x 20ml) and brine (1 x 20ml). The solution was dried over MgSO4 , filtered and concentrated. The crude product was purified via radial chromatography (3:1 hexanes-EtOAc) to afford 282 mg of the hydroxy ester (plus a small amount of impurity), which was carried on directly to the next step.
向冷却至0℃的搅拌着的粗羟基酯(282mg，0.48mmol)的吡啶溶液中滴加异丁酰氯(0.2ml，1.92mmol)。除去冷却浴，将混合物搅拌5小时。加入水(2ml)，将混合物搅拌另外30分钟。溶液用乙醚萃取(3×10ml)。将乙醚层连续用冰冷的1N HCl(2×10ml)、饱和NaHCO3(1×10ml)和盐水(1×10ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。粗产物经由径向色谱纯化(4∶1己烷-EtOAc)，得到171mg异丁酰基酯138(两步总收率23％)。To a stirred solution of the crude hydroxyester (282mg, 0.48mmol) in pyridine cooled to 0°C was added dropwise isobutyryl chloride (0.2ml, 1.92mmol). The cooling bath was removed and the mixture was stirred for 5 hours. Water (2ml) was added and the mixture was stirred for a further 30 minutes. The solution was extracted with ether (3 x 10ml). The ether layer was washed successively with ice-cold 1N HCl (2×10 ml), saturated NaHCO 3 (1×10 ml) and brine (1×10 ml). The solution was dried over MgSO4 , filtered and concentrated. The crude product was purified via radial chromatography (4:1 hexane-EtOAc) to afford 171 mg of isobutyryl ester 138 (23% over two steps).
按照前述标准的BOC-去保护条件除去该酯的BOC基团，得到所需的胺139。 Removal of the BOC group of the ester affords the desired amine 139 following the standard BOC-deprotection conditions previously described.
胺145的制备Preparation of Amine 145
如流程39所述制备该胺。将羟基酯140(M.Shimano等《四面体》1998，54，12745)(6.27mmol)溶于15ml DMF，冷却至0℃。向该溶液中连续加入DMAP(1.53g，12.53mmol)、EDCI(1.8g，9.40mmol)和N-BOC-O-Bn-(L)-苏氨酸(2.52g，8.15mmol)。使反应物温热至室温，搅拌过夜。将溶液倒在迅速搅拌着的30ml冰冷的0.5N HCl与50ml4∶1己烷-乙醚的混合物中。分离各层，含水层用4∶1己烷-乙醚萃取(1×30ml)。合并后的有机层用0.5N HCl(1×20ml)和盐水(2×20ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。粗物质经过硅胶(150g)色谱纯化，用1.25L 3∶1 CH2Cl2-己烷洗脱茴香醛，然后用65∶10∶25 CH2Cl2-乙醚-己烷洗脱偶联产物141(3.95g，88％)。The amine was prepared as described in Scheme 39. Hydroxyl ester 140 (M. Shimano et al. "Tetrahedron" 1998, 54, 12745) (6.27 mmol) was dissolved in 15 ml of DMF and cooled to 0°C. To this solution were successively added DMAP (1.53 g, 12.53 mmol), EDCI (1.8 g, 9.40 mmol) and N-BOC-O-Bn-(L)-threonine (2.52 g, 8.15 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The solution was poured into a rapidly stirred mixture of 30 mL of ice-cold 0.5N HCl and 50 mL of 4:1 hexane-ether. The layers were separated and the aqueous layer was extracted with 4:1 hexane-ether (1 x 30 mL). The combined organic layers were washed with 0.5N HCl (1 x 20ml) and brine (2 x 20ml). The solution was dried over MgSO4 , filtered and concentrated. The crude material was chromatographed on silica gel (150 g) eluting anisaldehyde with 1.25 L of 3:1 CH2Cl2 - hexane, followed by coupling product 141 with 65:10:25 CH2Cl2 - ether-hexane (3.95 g, 88%).
在Parr设备内，将苄基醚141(1.32g，1.84mol)与200mg 10％Pd/C在25ml EtOAc中的混合物在50psi氢压下摇动5小时。将混合物通过C盐垫过滤，浓缩，得到羟基酸142(680mg，70％)，NMR分析证实是相当纯的。A mixture of benzyl ether 141 (1.32 g, 1.84 mol) and 200 mg 10% Pd/C in 25 ml EtOAc was shaken under 50 psi hydrogen pressure for 5 hours in a Parr apparatus. The mixture was filtered through a pad of Celite(R ) and concentrated to afford hydroxyacid 142 (680 mg, 70%) which was confirmed to be fairly pure by NMR analysis.
向搅拌着的羟基酸142(1.54g，2.86mmol)与苄基溴(1.5ml，12.29mmol)的7ml DMF溶液中加入固体碳酸氢钠(1.2g，14.27mmol)。将混合物在室温下搅拌24小时，然后在25ml水与10ml4∶1己烷-乙醚之间分配。分离各层，含水层用4∶1己烷-乙醚萃取(2×10ml)。合并后的有机层用0.1N NaOH(1×10ml)和水(1×10ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。粗物质经由径向色谱纯化(4∶1己烷-EtOAc)，得到1.04g(60％)羟基苄基酯143。To a stirred solution of hydroxyacid 142 (1.54g, 2.86mmol) and benzyl bromide (1.5ml, 12.29mmol) in 7ml DMF was added solid sodium bicarbonate (1.2g, 14.27mmol). The mixture was stirred at room temperature for 24 hours, then partitioned between 25 mL of water and 10 mL of 4:1 hexane-ether. The layers were separated and the aqueous layer was extracted with 4:1 hexane-ether (2 x 10 mL). The combined organic layers were washed with 0.1N NaOH (1 x 10 ml) and water (1 x 10 ml). The solution was dried over MgSO4 , filtered and concentrated. The crude material was purified via radial chromatography (4:1 hexane-EtOAc) to afford 1.04 g (60%) of hydroxybenzyl ester 143 .
向搅拌着的酯143(840mg，1.34mmol)与乙酸酐(1.0ml，10.68mmol)的7ml吡啶溶液中加入DMAP(40mg，0.67mmol)。将反应物在室温下搅拌4小时，用80ml EtOAc稀释。将该溶液连续用饱和CuSO4(3×30ml)、1N HCl(1×30ml)、饱和NaHCO3(1×30ml)和盐水(1×30ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩，得到0.9g(100％)乙酸酯144，光谱分析证实是相当纯的。经由前述相似的步骤转化乙酸酯144，得到胺145。
2，3，4-三-O-烷基-β-D-吡喃木糖基胺147c，d，e2,3,4-Tri-O-alkyl-β-D-xylopyranosylamine 147c,d,e
这些胺的合成如流程40所示。向室温下的搅拌着的三乙酰氧基-2-叠氮基吡喃木糖基叠氮化物146(Acros Chemical Co.)的CH3OH溶液中加入1.1ml(1.06mmol)1.0M甲醇钠的甲醇溶液。将反应物搅拌过夜，用5×8-100酸性树脂(～0.6g)中和。将溶液过滤，浓缩。所得叠氮基三醇147a直接用于下面的步骤。The synthesis of these amines is shown in Scheme 40. To a stirred solution of triacetoxy-2-azidoxylopyranosyl azide 146 (Acros Chemical Co.) in CH 3 OH at room temperature was added 1.1 ml (1.06 mmol) of 1.0 M sodium methoxide methanol solution. The reaction was stirred overnight and neutralized with 5 x 8-100 acidic resin (-0.6 g). The solution was filtered and concentrated. The resulting azidotriol 147a was used directly in the next step.
将粗的三醇147a溶于15ml DMF，历时1 5分钟分四部分加入NaH(60％分散系，0.53g，13.28mmol)。将反应物在室温下搅拌30分钟，加入烯丙基溴(2.7ml，33.20mmol)，将混合物搅拌过夜。小心地加入饱和氯化铵(10ml)，然后加入50ml水。水溶液用乙酸乙酯萃取(3×30ml)。有机层连续用水(4×30ml)和盐水(2×30ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。粗物质经由径向色谱纯化(6∶1己烷-EtOAc)，得到753mg(77％)三-O-n-烯丙基-2-叠氮基吡喃木糖147b。Crude triol 147a was dissolved in 15 ml DMF and NaH (60% dispersion, 0.53 g, 13.28 mmol) was added in four portions over 15 min. The reaction was stirred at room temperature for 30 minutes, allyl bromide (2.7ml, 33.20mmol) was added and the mixture was stirred overnight. Sat. ammonium chloride (10ml) was added carefully, followed by 50ml of water. The aqueous solution was extracted with ethyl acetate (3 x 30ml). The organic layer was washed successively with water (4x30ml) and brine (2x30ml). The solution was dried over MgSO4 , filtered and concentrated. The crude material was purified via radial chromatography (6:1 Hex-EtOAc) to afford 753 mg (77%) of Tris-On-allyl-2-azidoxylopyranose 147b.
在1大气压氢下与150mg 10％Pd/C在40ml EtOAc中搅拌4小时，还原所得叠氮化物和烯丙基部分。将所得溶液通过C盐垫过滤，蒸发，得到定量收率的标题胺147c。The resulting azide and allyl moieties were reduced by stirring with 150 mg 10% Pd/C in 40 ml EtOAc for 4 h under 1 atm of hydrogen. The resulting solution was filtered through a pad of Celite® and evaporated to give the title amine 147c in quantitative yield.
胺147d的制备类似于147c，但是在烷基化步骤中使用苄基溴，然后如上所述还原叠氮化物为胺。Amine 147d was prepared analogously to 147c, but using benzyl bromide in the alkylation step followed by reduction of the azide to the amine as described above.
类似地在1大气压氢下用10％Pd/C在EtOAc中氢化叠氮化物146，得到胺147e。Similar hydrogenation of azide 146 with 10% Pd/C in EtOAc under 1 atm of hydrogen affords amine 147e.
2，3，4-三-O-乙酰基-β-L-吡喃岩藻糖基(fucopyranosy)胺(148) 2,3,4-Tri-O-acetyl-β-L-fucopyranosyl (fucopyranosy)amine (148)
向2，3，4-三-O-乙酰基-β-L-吡喃岩藻糖基叠氮化物(Acros)(750mg，2.38mmol)的40ml EtOAc溶液中加入120mg 10％ Pd/C。将该溶液在氢气氛(1atm)下搅拌3小时。将混合物通过C盐垫过滤，垫子用EtOAc(25ml)洗涤。蒸发溶液，得到所需的胺148(688mg，100％)。To a solution of 2,3,4-tri-O-acetyl-β-L-fucopyranosyl azide (Acros) (750 mg, 2.38 mmol) in 40 ml EtOAc was added 120 mg 10% Pd/C. The solution was stirred under hydrogen atmosphere (1 atm) for 3 hours. The mixture was filtered through a pad of Celite® and the pad was washed with EtOAc (25ml). The solution was evaporated to afford the desired amine 148 (688 mg, 100%).
1，3，4，6-四-O-乙酰基-2-氨基-2-脱氧-α-D-吡喃葡萄糖(149)
向1，3，4，6-四-O-乙酰基-2-叠氮基-2-脱氧-α-D-吡喃葡萄糖(TCI-US)(300mg，0.80mmol)的25ml EtOAc溶液中加入180mg 10％Pd/C。将该溶液在氢气氛(1atm)下搅拌3小时。将混合物通过C盐垫过滤，垫子用EtOAc(20ml)洗涤。蒸发溶液，得到所需的胺149(282mg，100％)。To a solution of 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-α-D-glucopyranose (TCI-US) (300 mg, 0.80 mmol) in 25 ml EtOAc was added 180 mg 10% Pd/C. The solution was stirred under hydrogen atmosphere (1 atm) for 3 hours. The mixture was filtered through a pad of Celite® and the pad was washed with EtOAc (20ml). The solution was evaporated to afford the desired amine 149 (282 mg, 100%).
苄基与甲基3-氨基-三脱氧-L-吡喃阿拉伯己糖苷 150a和 150b 经由L.Daley等《合成通讯》1998，28，61的方法合成这些胺。 Benzyl and methyl 3-amino-trideoxy-L-arabinohexopyranoside 150a and 150b These amines were synthesized by the method of L. Daley et al.
胺153的制备Preparation of amine 153
如流程41所示制备该胺。如M.Shimano等《四面体》1998，54，12745所述制备[(3S，7R，8R，9S)-7-苄基-8-羟基-9-甲基-2，6-二氧代-[1，5]二氧杂环壬烷-3-基]氨基甲酸叔丁酯(151)。历时5分钟向搅拌着的该酯(120mg，0.30mmol)的吡啶(5ml)溶液中缓慢加入异丁烯酰氯(0.10ml，1.0mmol)。将所得混合物在室温N2气氛下搅拌过夜。使反应混合物在EtOAc(75ml)与1N HCl(50ml)之间分配。将有机层用水洗涤，然后用饱和NaCl洗涤，经MgSO4干燥，浓缩，得到澄清的油。该粗的油经过硅胶色谱纯化，用含30％ EtOAc的己烷作为洗脱剂，得到酰基化的中间体 152(138mg)，为澄清的玻璃物。如上述参考文献所述除去该中间体中的BOC基团，得到标题胺 153。The amine was prepared as shown in Scheme 41. [(3S, 7R, 8R, 9S)-7-benzyl-8-hydroxyl-9-methyl-2,6-dioxo- [1,5]Dioxanan-3-yl]carbamate tert-butyl ester (151). To a stirred solution of the ester (120mg, 0.30mmol) in pyridine (5ml) was added methacryloyl chloride (0.10ml, 1.0mmol) slowly over 5 minutes. The resulting mixture was stirred overnight at room temperature under N2 atmosphere. The reaction mixture was partitioned between EtOAc (75ml) and 1N HCl (50ml). The organic layer was washed with water, then saturated NaCl, dried over MgSO4 , concentrated to give a clear oil. The crude oil was purified by silica gel chromatography using 30% EtOAc in hexanes as eluent to afford the acylated intermediate 152 (138 mg) as a clear glass. Removal of the BOC group in this intermediate as described in the above reference affords the title amine 153 .
抗霉素A3的苯胺(154)的制备 Preparation of Aniline (154) of Antimycin A 3
向冷却至0℃的搅拌着的抗霉素A3(25mg，0.048mmol)的2.5mlCH2Cl2溶液中加入吡啶(11L)和PCl5(27mg，0.13mmol)。将混合物回流1.5小时，然后冷却至-30℃，加入甲醇(2.5ml)，使混合物温热至室温，搅拌过夜。将溶液倒在13ml CH2Cl2与13ml饱和碳酸氢钠的0℃混合物中。在分液漏斗中摇动混合物，分离各层。含水层用CH2Cl2萃取(2×5ml)，将合并后的有机层干燥(MgSO4)，过滤，浓缩，得到抗霉素A3的苯胺。To a stirred solution of antimycin A3 (25 mg, 0.048 mmol) in 2.5 ml CH2Cl2 cooled to 0 °C was added pyridine (11 L) and PCl5 (27 mg, 0.13 mmol). The mixture was refluxed for 1.5 hours, then cooled to -30°C, methanol (2.5ml) was added, the mixture was allowed to warm to room temperature and stirred overnight. The solution was poured into a 0°C mixture of 13 ml CH2Cl2 and 13 ml saturated sodium bicarbonate. Shake the mixture in a separatory funnel and separate the layers. The aqueous layer was extracted with CH2Cl2 (2 x 5ml) and the combined organic layers were dried ( MgSO4 ), filtered and concentrated to afford the aniline of Antimycin A3 .
关于胺与邻-羟基杂芳族羧酸偶联生成杂环芳族酰胺2的通用操作A general procedure for the coupling of amines with o-hydroxyheteroaromatic carboxylic acids to generate heterocyclic aromatic amides 2
偶联操作A：N-(2-(4-氯苯基)乙基)-3-羟基吡啶-2-甲酰胺(233)的制备
将在氩下搅拌着的3-羟基吡啶-2-羧酸(1.39g，0.01mol)在无水THF(60ml)中的混合物冷却至-20℃。向其中一齐加入20％光气的甲苯溶液(5.1g，0.01mol)，将所得混合物搅拌90分钟，同时温度缓慢升至0℃。然后将反应混合物重新冷却至-20℃，历时30分钟滴加二异丙基乙胺(2.58g，0.02mol)的THF(20ml)溶液。加入完全后，将混合物搅拌另外2小时，温度随之缓慢升至0℃。继续在0℃下搅拌过夜。向该搅拌着的混合物中一齐加入2-(4-氯苯基)乙胺(1.56g，0.01mol)，将所得混合物在室温下搅拌6小时。将混合物用乙醚(100ml)稀释，用1N HCl(100ml)洗涤，干燥(MgSO4)，浓缩，得到标题化合物，为不完全白色固体(1.95g)。质谱显示预期的3∶1母体离子比为m/e 276和278。A stirred mixture of 3-hydroxypyridine-2-carboxylic acid (1.39 g, 0.01 mol) in anhydrous THF (60 mL) under argon was cooled to -20°C. A 20% phosgene solution in toluene (5.1 g, 0.01 mol) was added all at once, and the resulting mixture was stirred for 90 minutes while the temperature was slowly raised to 0°C. The reaction mixture was then recooled to -20°C and a solution of diisopropylethylamine (2.58 g, 0.02 mol) in THF (20 ml) was added dropwise over 30 minutes. After the addition was complete, the mixture was stirred for an additional 2 hours, with which time the temperature was slowly raised to 0°C. Stirring was continued overnight at 0 °C. To the stirred mixture was added 2-(4-chlorophenyl)ethylamine (1.56 g, 0.01 mol) all at once, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was diluted with diethyl ether (100ml), washed with 1N HCl (100ml), dried ( MgSO4 ) and concentrated to afford the title compound as an off-white solid (1.95g). Mass spectra showed m/e 276 and 278 in the expected 3:1 precursor ion ratio.
偶联操作B：3-羟基-4-甲氧基-N-(4-(4-三氟甲基苯氧基)苯基)吡啶-2-甲酰胺(425)的制备 Coupling Procedure B: Preparation of 3-Hydroxy-4-methoxy-N-(4-(4-trifluoromethylphenoxy)phenyl)pyridine-2-carboxamide (425)
向搅拌着的4-(4-三氟甲基苯氧基)苯胺(0.20g，0.8mmol)与DMAP(0.10g，0.085mmol)的CH2Cl2(10ml)溶液中一齐加入3-苄氧基-6-溴-4-甲氧基吡啶-2-碳酰氯(3)(0.29g，0.8mmol)的CH2Cl2(5ml)溶液。将所得混合物在室温下搅拌过夜，然后倒在2N HCl(10ml)中。分离有机层，含水层用CH2Cl2萃取(2×10ml)。将有机层合并，干燥(MgSO4)，浓缩，得到胶状固体。将该固体溶于EtOAc(20ml)，加入三乙胺(0.80g，0.8mmol)和5％披钯碳(0.10g)。在Parr摇动器上使所得混合物受到氢气氛(最初压力＝50psi)处理达30分钟。将混合物过滤，用0.1N HCl(20ml)洗涤，干燥(MgSO4)，浓缩，得到标题化合物，为不完全白色固体(0.14g)，m.p.＝122-129℃。To a stirred solution of 4-(4-trifluoromethylphenoxy)aniline (0.20 g, 0.8 mmol) and DMAP (0.10 g, 0.085 mmol) in CH 2 Cl 2 (10 ml) was added 3-benzyloxy A solution of 6-bromo-4-methoxypyridine-2-carbonyl chloride (3) ( 0.29 g, 0.8 mmol) in CH2Cl2 (5 ml). The resulting mixture was stirred overnight at room temperature, then poured into 2N HCl (10 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 10ml). The organic layers were combined, dried ( MgSO4 ), and concentrated to give a gummy solid. This solid was dissolved in EtOAc (20ml) and triethylamine (0.80g, 0.8mmol) and 5% palladium on carbon (0.10g) were added. The resulting mixture was subjected to a hydrogen atmosphere (initial pressure = 50 psi) for 30 minutes on a Parr shaker. The mixture was filtered, washed with 0.1N HCl (20ml), dried ( MgSO4 ) and concentrated to afford the title compound as an off-white solid (0.14g), mp = 122-129°C.
偶联操作C：N-(4-环己基苯基)-3-羟基吡啶-2-甲酰胺的制备 Coupling Procedure C: Preparation of N-(4-cyclohexylphenyl)-3-hydroxypyridine-2-carboxamide
向搅拌着的3-羟基吡啶-2-羧酸(如前文所述，在Pd/C的存在下通过催化氢化作用从16得到)(0.42g，3mmol)与4-环己基苯胺(0.35g，2mmol)的无水DMF(5ml)溶液中连续加入1-羟基苯并三唑(0.48g)、EDCI(0.65g)和N-甲基吗啉(1.41g)。加入另外的DMF(5ml)，将反应混合物在室温下搅拌过夜。将混合物倒在水(200ml)中，然后用EtOAc萃取(2×75ml)。将有机萃取液合并，用水(100ml)和饱和NaCl溶液(50ml)洗涤，干燥(MgSO4)，浓缩。粗的油放置后固化，经过硅胶色谱纯化(4∶1石油醚-EtOAc)，得到标题化合物(0.42g)，为黄褐色固体，m.p.91-93℃。杂环芳族酰胺修饰为其他杂环芳族酰胺4-羟基噻吩-N-(3，3，5，5-四甲基环己基)-3-甲酰胺(554)的制备
按照前述通用偶联操作C将4-甲氧基噻吩羧酸和3，3，5，5-四甲基环己胺偶联在一起，得到4-甲氧基噻吩-N-(3，3，5，5-四甲基环己基)-3-甲酰胺。According to the aforementioned general coupling operation C, 4-methoxythiophene carboxylic acid and 3,3,5,5-tetramethylcyclohexylamine are coupled together to obtain 4-methoxythiophene-N-(3,3 , 5,5-Tetramethylcyclohexyl)-3-carboxamide.
将在干燥试管下的500mg该甲氧基噻吩酰胺的15ml氯仿溶液在干冰-丙酮浴中搅拌5分钟。历时15分钟向该溶液中滴加940mg三溴化硼(2当量)的10ml氯仿溶液。继续搅拌，同时使反应混合物温热至室温，然后过夜。然后将反应混合物放入冷水浴中，滴加15ml水。搅拌15分钟后，将混合物用50ml CH2Cl2稀释，分离有机层。水层用50mlCH2Cl2洗涤。将合并后的有机萃取液用25ml水和饱和盐水溶液洗涤，干燥。将萃取液过滤并浓缩。残余物经过硅胶色谱纯化，用CH2Cl2-5％EtOAc作为洗脱剂，得到310mg标题化合物，为黄褐色晶体，m.p.170-174℃。样本从石油醚-EtOAc中重结晶，得到黄褐色针晶，m.p.171-173℃。
偶联中间体156a-d的制备Preparation of Coupling Intermediates 156a-d
如流程42所述制备这些中间体。These intermediates were prepared as described in Scheme 42.
历时5分钟向搅拌着的盐酸(±)-丝氨酸的异丙基酯(2.75g)与三乙胺(3.55g)的CH2Cl2(75ml)溶液中加入3-苄氧基-6-溴-4-甲氧基吡啶-2-碳酰氯(3)(5.32g)的CH2Cl2(15ml)溶液。将混合物在室温下搅拌30分钟，然后倒在1N HCl(75ml)中。分离有机层，用水(25ml)洗涤，干燥(Na2SO4)，蒸发溶剂，得到黄色胶状物(6.7g)。该物质能够从乙醚/己烷中重结晶，得到 155a，为白色固体，m.p.100-103℃。从盐酸(±)-丝氨酸的甲基酯开始的类似操作得到甲基酯中间体 155b。To a stirred solution of (±)-serine isopropyl hydrochloride (2.75 g) and triethylamine (3.55 g) in CH2Cl2 (75 ml) was added 3-benzyloxy-6-bromo over 5 minutes - A solution of 4-methoxypyridine-2-carbonyl chloride (3) (5.32 g) in CH2Cl2 (15 ml). The mixture was stirred at room temperature for 30 minutes, then poured into 1N HCl (75ml). The organic layer was separated, washed with water (25ml), dried ( Na2SO4 ) and the solvent was evaporated to give a yellow gum (6.7g). This material could be recrystallized from ether/hexanes to afford 155a as a white solid, mp 100-103°C. A similar procedure starting from the methyl ester of (±)-serine hydrochloride afforded the methyl ester intermediate 155b .
向搅拌着的155a(1.17g)、三乙胺(0.31g)与DMAP(0.06g)的CH2Cl2(25ml)溶液中一次性加入α-甲基氢化肉桂酰氯(0.46g)。将所得混合物在室温下搅拌4小时，然后倒在2N HCl(15ml)中。分离有机相，用1N NaOH(15ml)洗涤，干燥(MgSO4)，蒸发溶剂，得到 156a，为黄色的油(1.45g)。NMR(CDCl3)与该油的1∶1非对映体混合物是一致的。To a stirred solution of 155a (1.17g), triethylamine (0.31g) and DMAP (0.06g) in CH2Cl2 ( 25ml ) was added α-methylhydrocinnamoyl chloride (0.46g) in one portion. The resulting mixture was stirred at room temperature for 4 hours, then poured into 2N HCl (15ml). The organic phase was separated, washed with 1N NaOH (15ml), dried ( MgSO4 ) and the solvent evaporated to give 156a as a yellow oil (1.45g). NMR ( CDCl3 ) was consistent with a 1:1 mixture of diastereomers of the oil.
将3-(叔丁基二甲基甲硅烷氧基)丁酰氯(3.55g)(通过A.Wissner和C.V.Grudzinskas《有机化学杂志》1978，43，3972的方法从相应的叔丁基二甲基甲硅烷基酯制备)的CH2Cl2(10ml)溶液迅速加入到冷(0℃)的搅拌着的155b(6.6g)与DMAP(0.18g)的无水吡啶(25ml)溶液中。将反应混合物在0℃下搅拌15分钟，然后在室温下搅拌3小时。用乙醚(200ml)稀释后，将混合物用水萃取(2×100ml)，干燥(MgSO4)，蒸发溶剂。向残余物中加入甲苯(25ml)，再次蒸发溶剂。黄色油性残余物经由色谱纯化(硅胶，7∶3己烷/丙酮)，得到156b，为非对映体的混合物。3-(tert-butyldimethylsilyloxy)butyryl chloride (3.55 g) (from the corresponding tert-butyldimethylformazan by the method of A. Wissner and CV Grudzinskas "Journal of Organic Chemistry" 1978,43,3972 Silyl ester preparation) in CH2Cl2 ( 10ml ) was rapidly added to a cold (0°C) stirred solution of 155b (6.6g) and DMAP (0.18g) in anhydrous pyridine (25ml). The reaction mixture was stirred at 0 °C for 15 minutes, then at room temperature for 3 hours. After dilution with diethyl ether (200ml), the mixture was extracted with water (2x100ml), dried ( MgSO4 ) and the solvent was evaporated. Toluene (25ml) was added to the residue, and the solvent was evaporated again. The yellow oily residue was purified by chromatography (silica gel, 7:3 hexane/acetone) to afford 156b as a mixture of diastereomers.
向搅拌着的2-苄基-3-(叔丁基二甲基甲硅烷氧基)丙酸(7.36g)(N.P.Peet，N.L.Lentz，M.W.Dudley，A.M.L.Ogden，D.E.McCarty和M.M.Racke《医药化学杂志》1993，36，4015)的DMF(20ml)溶液中一齐加入叔丁基二甲基甲硅烷基氯(4.52g)，然后加入咪唑(4.1g)，将所得混合物在室温下搅拌24小时。将混合物用水(300ml)稀释，然后用戊烷萃取(3×100ml)。将戊烷相用水洗涤，干燥(Na2SO4)，蒸发溶剂，得到无色的油(9.5g)。NMR(CDCl3)与该油的非对映体混合物是一致的。通过N.P.Peete等《有机化学杂志》1978，43，3972的方法将该酯(4.1g)转化为相应的酰氯。如上所述使该酯(4.1g)与 155b(4.4g)缩合，硅胶色谱纯化(4∶1己烷/丙酮)后得到所需的 156c，为非对映体的混合物。To stirred 2-benzyl-3-(tert-butyldimethylsilyloxy)propionic acid (7.36g) (NPPeet, NLLentz, MWDudley, AMLOgden, DEMcCarty and MMRacke "Journal of Medicinal Chemistry" 1993,36, 4015) in DMF (20 ml) were added all at once tert-butyldimethylsilyl chloride (4.52 g), then imidazole (4.1 g), and the resulting mixture was stirred at room temperature for 24 hours. The mixture was diluted with water (300ml) and extracted with pentane (3x100ml). The pentane phase was washed with water , dried ( Na2SO4 ) and the solvent was evaporated to give a colorless oil (9.5g). NMR ( CDCl3 ) was consistent with a diastereomeric mixture of the oil. The ester (4.1 g) was converted to the corresponding acid chloride by the method of NPPeete et al. J. Org. Chem. 1978, 43, 3972. Condensation of this ester (4.1 g) with 155b (4.4 g) as described above gave the desired 156c as a mixture of diastereomers after silica gel chromatography (4:1 hexane/acetone).
向搅拌着的156c(4.5g)的甲醇(35ml)溶液中加入浓HCl(1.5ml)。将所得混合物在室温下搅拌30分钟，用水(200ml)稀释，然后用CH2Cl2萃取(2×100ml)。将有机相干燥(MgSO4)，蒸发溶剂。残余物经由硅胶色谱纯化(7∶3己烷/丙酮)，得到 156d，为淡黄色胶状物(2.8g)。NMR(CDCl3)显示它是非对映体的混合物。To a stirred solution of 156c (4.5g) in methanol (35ml) was added concentrated HCl (1.5ml). The resulting mixture was stirred at room temperature for 30 minutes, diluted with water (200ml) and extracted with CH2Cl2 ( 2x100ml ). The organic phase was dried ( MgSO4 ) and the solvent was evaporated. The residue was purified via silica gel chromatography (7:3 hexanes/acetone) to afford 156d as a pale yellow gum (2.8 g). NMR ( CDCl3 ) showed it to be a mixture of diastereomers.
如前文所述，在Pd/C的存在下通过氢化作用将156a-d转化为相应的去保护的杂环芳族酰胺。 156a-d were converted to the corresponding deprotected heterocyclic aromatic amides by hydrogenation in the presence of Pd/C as previously described.
中间体158的制备Preparation of Intermediate 158
该中间体的合成如流程43所示。按照通用偶联操作B，在CH2Cl2(150ml)中从(+)-反式-1-羟基-2-氨基环戊烷氢溴酸盐(7.09g，38.9mmol)和3-苄氧基-6-溴-4-甲氧基吡啶-2-碳酰氯(3)(13.8g，38.9mmol)制备酰胺 157，经过快速色谱纯化，用1∶1己烷-EtOAc作为洗脱剂。得到 157(13.4g)，为白色固体，m.p.56-57℃。The synthesis of this intermediate is shown in Scheme 43. From (+)-trans-1 - hydroxy- 2 -aminocyclopentane hydrobromide (7.09 g, 38.9 mmol) and 3-benzyloxy Amide 157 was prepared from yl-6-bromo-4-methoxypyridine-2-carbonyl chloride (3) (13.8 g, 38.9 mmol) and purified by flash chromatography using 1:1 hexane-EtOAc as eluent. 157 was obtained (13.4 g) as a white solid, mp 56-57°C.
将二甲基亚砜(7.4ml，104.1mmol)缓慢加入到-78℃的草酰氯(4.54ml，52.08mmol)的CH2Cl2(100ml)溶液中，然后加入酰胺157(10.46g，24.8mmol)的CH2Cl2(25ml)溶液。30分钟后，加入Et3N，使溶液缓慢温热至室温。将混合物倒在饱和NH4Cl(100ml)中，用CH2Cl2萃取(2×100ml)。将合并后的有机层用盐水洗涤，干燥，蒸发溶剂。残余物经由柱色谱纯化，用1∶1 EtOAc-己烷作为洗脱剂，得到酮158(9.64g，94％)，GC/MS和1H-NMR证实是纯的。Dimethylsulfoxide (7.4ml, 104.1mmol) was slowly added to a solution of oxalyl chloride (4.54ml, 52.08mmol) in CH2Cl2 ( 100ml ) at -78°C, followed by the addition of amide 157 (10.46g, 24.8mmol ) in CH2Cl2 ( 25ml ). After 30 min, Et3N was added and the solution was allowed to warm slowly to room temperature. The mixture was poured into saturated NH4Cl (100ml) and extracted with CH2Cl2 ( 2x100ml ). The combined organic layers were washed with brine, dried and the solvent was evaporated. The residue was purified by column chromatography using 1:1 EtOAc-hexanes as eluent to afford ketone 158 (9.64 g, 94%), which was confirmed to be pure by GC/MS and1H -NMR.
如前文所述，在Pd/C的存在下通过氢化作用将 157和 158都转化为相应的去保护的杂环芳族酰胺。 Both 157 and 158 were converted to the corresponding deprotected heterocyclic aromatic amides by hydrogenation in the presence of Pd/C as previously described.
中间体160a-d的制备Preparation of Intermediates 160a-d
如流程44制备这些中间体。按照通用偶联操作C使丝氨醇与3-苄氧基-6-溴-4-甲氧基吡啶甲酸(16)偶联，得到1，3-二醇159，为无色的油，1H、13C-NMR和IR光谱证实是纯的。These intermediates were prepared as in Scheme 44. Coupling of serinol with 3-benzyloxy-6-bromo-4-methoxypicolinic acid (16) following general coupling procedure C afforded 1,3-diol 159 as a colorless oil, 1 H, 13 C-NMR and IR spectra confirmed purity.
在迪安斯塔克设备内，在催化量对-甲苯磺酸(0.1mmol)的存在下，在甲苯(20ml/mmol)中回流使1，3-二醇 159(1mmol)与适当的羰基化合物(2mmol)或相应的二甲基乙缩醛(2mmol)缩合。1,3-diol 159 (1 mmol) was reacted with the appropriate carbonyl compound at reflux in toluene (20 ml/mmol) in the presence of a catalytic amount of p-toluenesulfonic acid (0.1 mmol) in a Dean Stark apparatus. (2mmol) or the corresponding dimethyl acetal (2mmol) condensation.
因而， 159与1，3，3-三甲氧基丙烷的缩合得到缩醛 160a，为顺式与反式非对映体的2∶1混合物。质谱(ES)显示[M+]在(m/e)495和497。1H、13C-NMR和IR光谱与结构160a是一致的。Thus, condensation of 159 with 1,3,3-trimethoxypropane gave acetal 160a as a 2:1 mixture of cis and trans diastereomers. Mass spectrum (ES) showed [M + ] at (m/e) 495 and 497. 1 H, 13 C-NMR and IR spectra were consistent with structure 160a.
159与2-甲基-3-(4-叔丁基)苯基丙酮的缩合得到缩醛 160b，为顺式与反式非对映体的3∶1混合物。质谱(ES)显示[M+]在(m/e)597。1H、13C-NMR和IR光谱与结构160b是一致的。Condensation of 159 with 2-methyl-3-(4-tert-butyl)phenylacetone afforded acetal 160b as a 3:1 mixture of cis and trans diastereomers. Mass spectrum (ES) showed [M + ] at (m/e)597. 1 H, 13 C-NMR and IR spectra were consistent with structure 160b.
159与二氢-β-紫罗兰酮的缩合得到缩醛 160c，为顺式与反式非对映体的2∶1混合物。质谱(ES)显示[M+]在(m/e)587。1H、13C-NMR和IR光谱与结构160c是一致的。Condensation of 159 with dihydro-β-ionone afforded acetal 160c as a 2:1 mixture of cis and trans diastereomers. Mass spectrum (ES) showed [M + ] at (m/e)587. 1 H, 13 C-NMR and IR spectra were consistent with structure 160c.
159与3，3，5，5-四甲基环己酮的缩合得到缩醛 160d，1H、13C-NMR和IR光谱证实是一致的。Condensation of 159 with 3,3,5,5-tetramethylcyclohexanone gave acetal 160d , which was confirmed by 1 H, 13 C-NMR and IR spectra.
如前文所述，在Pd/C的存在下通过氢化作用将中间体 160a-d转化为相应的去保护的杂环芳族酰胺。 Intermediates 160a-d were converted to the corresponding deprotected heterocyclic aromatic amides by hydrogenation in the presence of Pd/C as previously described.
化合物 280和 281的制备Preparation of Compounds 280 and 281
流程45描述这些化合物的制备。因而，首先利用标准的偶联操作C使2，3，6，6-四甲基-2-环庚烯基胺与2-羟基-3-甲氧基-2-吡啶甲酸偶联，得到中间体
161。按照《四面体快报》1991，32，1831-1834的操作进行化合物
161的二氯化作用，得到二氯衍生物
281。在CH2Cl2中进行
161的标准m-CPBA氧化作用，得到含有N-氧化物的环氧类似物
162，在标准的催化氢化条件下用H2(45psi)和10％Pd/C处理，生成化合物
280。
反式-4-羟基-3，3，5，5-四甲基吡啶酰胺(264)的制备Preparation of trans-4-hydroxy-3,3,5,5-tetramethylpyridinamide (264)
如流程46所示制备该化合物。向搅拌着的酮基-吡啶酰胺266(56mg，0.18mmol)的2ml甲醇溶液中加入硼氢化钠(20mg，0.53mmol)。将反应物搅拌5小时，蒸发甲醇。将粗物质用5ml水稀释，用EtOAc萃取(3×5ml)。有机层用水(1×5ml)和盐水(1×5ml)洗涤。将溶液经MgSO4干燥，过滤，浓缩。NMR和GC分析结果与标题化合物264是一致的，具有反式立体化学，纯度为95％。
化合物341的制备Preparation of Compound 341
该化合物的制备如流程47所述。将苄基酯前体139(流程38)(33mg，0.046mmol)溶于10ml EtOAc，加入110mg Pearlman催化剂。在Parr仪器内将混合物在50psi氢压下摇动12小时。然后将溶液过滤并浓缩。然后将残余物溶于少量乙醚，加入石油醚，直至有沉淀生成。过滤收集固体，干燥，得到标题化合物341。The preparation of this compound is described in Scheme 47. Benzyl ester precursor 139 (Scheme 38) (33 mg, 0.046 mmol) was dissolved in 10 ml EtOAc and 110 mg Pearlman catalyst was added. The mixture was shaken for 12 hours under 50 psi hydrogen pressure in a Parr apparatus. The solution was then filtered and concentrated. The residue was then dissolved in a small amount of ether, and petroleum ether was added until a precipitate formed. The solid was collected by filtration and dried to afford the title compound 341.
N-(3-羟基-4-甲氧基-2-吡啶基羰基)-2-氨基-2-脱氧-α-D-吡喃葡萄糖(334)的制备
利用标准偶联操作C使1，3，4，6-四-O-乙酰基-2-氨基-2-脱氧-α-D-吡喃葡萄糖(151)与3-羟基-4-甲氧基吡啶甲酸偶联在一起。向所得吡啶酰胺(0.19g，0.38mmol)的6ml甲醇溶液中加入氢氧化锂一水合物(0.92mmol，40mg)。将反应混合物在室温下搅拌过夜。加入DOWEX5×8-100酸性树脂(0.5g)中和溶液。将混合物过滤，浓缩，得到标题化合物(110mg，88％)。
外环酯166a、氨基甲酸酯166b和碳酸酯166c的通用制备General preparation of exocyclic ester 166a, carbamate 166b and carbonate 166c
一般如流程48所述制备这些化合物，从胺164开始，按照M.Shimano等《四面体》1998，54，12745的操作制备。按照前述标准偶联操作C使该胺与3-苄氧基-6-溴-4-甲氧基吡啶甲酸16偶联，然后在碱的存在下使所得中间体165与适当的羧酸酰氯、烷基异氰酸酯或烷基氯甲酸酯反应，分别得到所需的被保护的酯166a、氨基甲酸酯166b和碳酸酯166c。按照前述操作在Pd/C的存在下用H2去保护这些化合物，得到所需的酯、氨基甲酸酯和碳酸酯。上述步骤也用于制备其他类似的酯、氨基甲酸酯和碳酸酯。These compounds were generally prepared as described in Scheme 48, starting from amine 164, following the procedure of M. Shimano et al. Tetrahedron 1998, 54, 12745. The amine is coupled with 3-benzyloxy-6-bromo-4-methoxypicolinic acid 16 following the standard coupling procedure C previously described, and the resulting intermediate 165 is then reacted with the appropriate carboxylic acid chloride, Reaction of an alkyl isocyanate or alkyl chloroformate affords the desired protected ester 166a, carbamate 166b and carbonate 166c, respectively. Deprotection of these compounds with H2 in the presence of Pd/C following the previous procedure afforded the desired esters, carbamates and carbonates. The above procedure is also used to prepare other similar esters, carbamates and carbonates.
166a的制备Preparation of 166a
历时5分钟向搅拌着的 165(180mg，0.29mmol)的吡啶(10ml)溶液中缓慢加入环丙烷碳酰氯(0.45ml，5mmol)。将混合物在室温N2气氛下搅拌过夜。将所得混合物倒在1N HCl(30ml)中，用EtOAc萃取(2×75ml)。将有机层合并，用水(25ml)洗涤，然后用饱和NaCl(25ml)洗涤，经MgSO4干燥，浓缩，得到橙色的油。粗油经过硅胶色谱纯化，用含30％至50％EtOAc的己烷梯度作为洗脱剂，得到标题化合物166a(100mg)，为澄清的油。To a stirred solution of 165 (180 mg, 0.29 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (0.45 mL, 5 mmol) slowly over 5 minutes. The mixture was stirred overnight at room temperature under N2 atmosphere. The resulting mixture was poured into 1N HCl (30ml) and extracted with EtOAc (2 x 75ml). The organic layers were combined, washed with water (25ml), then saturated NaCl (25ml), dried over MgSO4 and concentrated to give an orange oil. The crude oil was purified by silica gel chromatography using a gradient of 30% to 50% EtOAc in hexanes as eluent to afford the title compound 166a (100 mg) as a clear oil.
166b的制备Preparation of 166b
向搅拌着的 165(200mg，0.33mmol)的CH2Cl2(5ml)溶液中加入三乙胺(2滴)、DMAP(1mg)和异氰酸异丙酯(0.2ml，2mmol)。将所得混合物在室温氮气氛下搅拌过夜。将反应混合物倒在1N HCl(25ml)中，用EtOAc萃取(2×50ml)。将有机层合并，用水洗涤，然后用饱和NaCl洗涤，经MgSO4干燥，浓缩，得到粉红色泡沫。粗泡沫经过硅胶色谱纯化，用含30％至50％EtOAc的己烷梯度作为洗脱剂，得到标题化合物166b(90mg)，为白色固体。To a stirred solution of 165 (200 mg, 0.33 mmol) in CH2Cl2 (5 ml) was added triethylamine (2 drops), DMAP (1 mg) and isopropyl isocyanate (0.2 ml, 2 mmol). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was poured into 1N HCl (25ml) and extracted with EtOAc (2 x 50ml). The organic layers were combined, washed with water, then saturated NaCl, dried over MgSO4 , concentrated to give a pink foam. The crude foam was chromatographed on silica gel using a gradient of 30% to 50% EtOAc in hexanes as eluent to afford the title compound 166b (90 mg) as a white solid.
166c的制备Preparation of 166c
在氮气氛下将搅拌着的
165(180mg，0.29mmol)的吡啶(5ml)与CH2Cl2(5ml)溶液在冰浴中冷却至0℃。历时1分钟向冷却的混合物中缓慢加入氯甲酸异丙酯(1M甲苯溶液，5ml)。除去冰浴，将混合物在室温下搅拌过夜。使反应混合物在1N HCl(25ml)与EtOAc(75ml)之间分配。将有机层用水洗涤，然后用饱和NaCl洗涤，经MgSO4干燥，浓缩，得到澄清的油。粗油经过硅胶色谱纯化，用含30％至50％EtOAc的己烷梯度作为洗脱剂，得到标题化合物166c(80mg)，为澄清的油。
中间体 167和 168的制备Preparation of intermediates 167 and 168
使如前所述得到的胺53的非对映体混合物(流程9)与酰氯3经由前述通用偶联操作A(流程49)偶联，得到非对映体 167与 168的混合物。通过小心的硅胶色谱法(85∶15己烷/丙酮)分离它们，得到纯的 167和 168，各自的收率约35％。如前文所述在Pd/C的存在下用H2去保护它们。Coupling of the diastereomeric mixture of amine 53 (Scheme 9) obtained as previously described with acid chloride 3 via the general coupling procedure A (Scheme 49) described above affords a mixture of diastereomers 167 and 168 . They were separated by careful silica gel chromatography (85:15 hexane/acetone) to give pure 167 and 168 in approximately 35% yield each. They were deprotected with H2 in the presence of Pd/C as previously described.
关于杂环芳族酰胺(2)转化为O-酰基杂环芳族酰胺(2Y：M＝酰基)、O-甲硅烷基杂环芳族酰胺(2Y：M＝甲硅烷基)和O-磺酰基杂环芳族酰胺(2Y：M＝磺酰基)的通用操作 Regarding the conversion of heterocyclic aromatic amides (2) to O-acyl heterocyclic aromatic amides (2Y: M = acyl), O-silyl heterocyclic aromatic amides (2Y: M = silyl) and O-sulfonic General Procedures for Acyl Heterocyclic Aromatic Amides (2Y: M = Sulfonyl)
O-(3，3-二甲基)丁酰化合物610的制备Preparation of O-(3,3-Dimethyl)butyryl Compound 610
该化合物的制备如流程50所述，从化合物169(按照M.Shimano等《四面体》1998，54，12745的操作制备)开始。因而，将搅拌着的化合物169(100mg，0.19mmol)与DMAP(5mg，0.04mmol)的无水吡啶(5ml)溶液用3，3-二甲基丁酰氯处理，将混合物在环境温度下搅拌5.5小时。然后将其用水(15ml)处理，用EtOAc(20ml)萃取。将有机萃取液连续用水和饱和含水NaHCO3洗涤，干燥(Na2SO4)，过滤，浓缩。经过硅胶制备型平板(2mm厚)色谱纯化，用乙醚洗脱，得到标题化合物，为不完全白色固体，m.p.151-152℃。1H-NMR和MS数据与指定结构是一致的。This compound was prepared as described in Scheme 50, starting from compound 169 (prepared according to the procedure of M. Shimano et al. Tetrahedron 1998, 54, 12745). Thus, a stirred solution of compound 169 (100 mg, 0.19 mmol) and DMAP (5 mg, 0.04 mmol) in anhydrous pyridine (5 ml) was treated with 3,3-dimethylbutyryl chloride and the mixture was stirred at ambient temperature for 5.5 Hour. It was then treated with water (15ml) and extracted with EtOAc (20ml). The organic extract was washed successively with water and saturated aqueous NaHCO3 , dried ( Na2SO4 ), filtered and concentrated. Chromatography on silica preparative plates (2 mm thick) eluting with diethyl ether afforded the title compound as an off-white solid, mp 151-152°C. 1 H-NMR and MS data were consistent with the assigned structure.
通过上述操作的变例制备其他O-酰基杂环芳族酰胺。这样的变例例如包括用本领域技术人员熟知的其他工艺纯化产物，例如柱色谱法或重结晶法。Other O-acyl heterocyclic aromatic amides were prepared by variations of the above procedure. Such variants include, for example, purification of the product by other techniques well known to those skilled in the art, such as column chromatography or recrystallization.
O-叔丁基二甲基甲硅烷基化合物720的制备Preparation of O-tert-butyldimethylsilyl compound 720
该化合物的制备如流程50所述。因而，将搅拌着的化合物169(100mg，0.19mmol)与N-甲基吗啉(0.13ml，1.18mmol)的无水DMF(2ml)溶液用叔丁基二甲基甲硅烷基氯(57mg，0.38mmol)处理，将混合物在环境温度下搅拌1天。使所得混合物在水(10ml)与EtOAc(15ml)之间分配，将有机相连续用饱和含水NaHCO3和盐水洗涤，干燥(Na2SO4)，过滤，浓缩。残余物经过快速硅胶柱色谱纯化，用乙醚洗脱，得到74mg标题化合物，为澄清油脂。1H-NMR光谱与指定结构是一致的。The preparation of this compound is described in Scheme 50. Thus, a stirred solution of compound 169 (100 mg, 0.19 mmol) and N-methylmorpholine (0.13 ml, 1.18 mmol) in anhydrous DMF (2 ml) was treated with tert-butyldimethylsilyl chloride (57 mg, 0.38 mmol) and the mixture was stirred at ambient temperature for 1 day. The resulting mixture was partitioned between water (10ml) and EtOAc ( 15ml), the organic phase was washed successively with saturated aqueous NaHCO3 and brine, dried ( Na2SO4 ), filtered and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ether, to give 74 mg of the title compound as a clear oil. 1 H-NMR spectrum was consistent with the assigned structure.
O-对-甲苯磺酰化合物722的制备Preparation of O-p-Toluenesulfonyl Compound 722
该化合物的制备如流程50所述。因而，将对-甲苯磺酰氯(90mg，0.466mmol)加入到搅拌着的化合物169(200mg，0.388mmol)与碳酸钾(65mg，0.466mmol)的无水丙酮(3ml)悬液中。在环境温度下搅拌12小时后，将混合物用EtOAc(25ml)稀释，用H2O洗涤(2×10ml)。将有机相干燥(MgSO4)，过滤，在真空中浓缩。残余物经过快速柱色谱纯化，用己烷-EtOAc(1∶1)洗脱，得到197mg白色固体，m.p.153-155℃，其1H-NMR光谱与所需标题化合物是一致的。The preparation of this compound is described in Scheme 50. Thus, p-toluenesulfonyl chloride (90mg, 0.466mmol) was added to a stirred suspension of compound 169 (200mg, 0.388mmol) and potassium carbonate (65mg, 0.466mmol) in anhydrous acetone (3ml). After stirring at ambient temperature for 12 hours, the mixture was diluted with EtOAc (25ml) and washed with H2O (2 x 10ml). The organic phase was dried ( MgSO4 ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with hexane-EtOAc (1:1) to afford 197 mg of white solid, mp 153-155°C, whose 1 H-NMR spectrum was consistent with the desired title compound.
表I阐述通过上述操作从适当原料制备的另外的式I化合物。关于所有这些化合物的1H-NMR光谱数据都与指定结构是一致的。Table I illustrates additional compounds of formula I prepared from appropriate starting materials by the procedures described above. 1 H-NMR spectral data for all these compounds were consistent with the assigned structures.
杀真菌剂的实用性Availability of fungicides
已经发现本发明的化合物可控制真菌，特别是植物病原体和腐蚀木材的真菌。在用于治疗植物真菌疾病时，向植物施用抑制疾病和植物学上可接受的量的化合物。施用可以在植物被真菌感染之前和/或之后进行。还可以通过处理植物种子、植物生长的土壤、播种用稻田或灌溉用水来进行施用。其他施用方式可以经由木材处理进行，以控制对木材和/或木材产品的破坏。The compounds of the present invention have been found to control fungi, especially phytopathogens and wood-corroding fungi. When used to treat fungal diseases of plants, the compound is applied to the plant in a disease inhibiting and phytologically acceptable amount. Application can be carried out before and/or after the plants are infected by the fungus. Application can also be performed by treating plant seeds, soil on which plants grow, paddy fields for sowing, or water for irrigation. Other modes of application can be via wood treatments to control damage to wood and/or wood products.
本文所用的术语“抑制疾病和植物学上可接受的量”指的是本发明化合物杀死或抑制植物病原体和预防、根除或阻止需要控制的植物疾病、但是对该植物没有显著毒性的量。这种量一般将从约1至1000ppm，10至500ppm是优选的。所需化合物的精确浓度因所要控制的真菌疾病、所采用的制剂类型、施用方法、特定的植物物种、气候条件和其他因素而异。适合的施用比例通常在约50至约1000克每公顷(g/Ha)的范围内。The term "disease-inhibiting and phyto-acceptable amount" as used herein refers to an amount of a compound of the present invention which kills or inhibits plant pathogens and prevents, eradicates or arrests a plant disease to be controlled, but which is not significantly toxic to the plant. Such amounts will generally be from about 1 to 1000 ppm, with 10 to 500 ppm being preferred. The precise concentration of compound required will vary depending on the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climatic conditions and other factors. Suitable application rates generally range from about 50 to about 1000 grams per hectare (g/Ha).
本发明化合物还可以用于保护所贮存的谷物和其他非植物部位不被真菌感染。The compounds of the invention may also be used to protect stored grain and other non-plant parts from fungal infection.
在实验室中进行下列实验，测定本发明化合物的杀真菌功效。The following experiments were carried out in the laboratory to determine the fungicidal efficacy of the compounds of the invention.
体外真菌生长抑制作用的生物学评价Biological Evaluation of Fungal Growth Inhibition in Vitro
培养条件：在无菌马铃薯葡萄糖肉汤(Difco)中制备Magnaporthegrisea(Pyriculariaoryzae-PYRIOR)、茄属丝核菌(Rhizoctoniasolani)(RHIZSO)、禾生球腔菌(Mycosphaerella graminicola)(小麦壳针孢(Septoria tritici)-SEPTTR)、Stagonosporanodorum(Leptosphaeria nodorum-LEPTNO)、玉蜀黍黑粉菌(Ustilago maydis)(USTIMA)的真菌分生狍子或菌丝片段的悬液，在黑麦种子肉汤中制备蔓延疫霉(Phytophthora infestans)(PHYTIN)的真菌分生狍子或菌丝片段的悬液。将悬液用移液管移入无菌的96孔微量滴定板中，平板中含有实验杀真菌剂样本的二甲基亚砜溶液。杀真菌剂的浓度从0.001至100ppm不等，最终溶剂浓度不超过培养基的1％。使真菌在24至30℃下生长不同时间间隔，直至在仅含有溶剂的对照孔中因真菌的生长而变浑浊。此时通过肉眼观察测定每孔的生长抑制作用，测定相对于溶剂处理对照而言的生长抑制百分比。Culture conditions: Magnaporthegrisea (Pyriculariaoryzae-PYRIOR), Rhizoctonia solani (RHIZSO), Mycosphaerella graminicola (Septoria tritici) were prepared in sterile potato dextrose broth (Difco). )-SEPTTR), Stagonosporanodorum (Leptosphaeria nodorum-LEPTNO), Ustilago maydis (USTIMA) fungal meristematic roe deer or suspension of mycelial fragments prepared in rye seed broth for Phytophthora infestans infestans) (PHYTIN) fungal meristematic roe deer or suspension of mycelial fragments. The suspension was pipetted into a sterile 96-well microtiter plate containing a solution of the test fungicide sample in dimethyl sulfoxide. The concentration of the fungicide varies from 0.001 to 100 ppm, and the final solvent concentration does not exceed 1% of the medium. The fungi were grown at 24 to 30°C for various time intervals until the control wells containing solvent only became cloudy due to fungal growth. At this point the growth inhibition of each well was determined by visual inspection and the percent growth inhibition relative to the solvent treated control was determined.
表II中，“+”表示试验材料产生至少80％的生长抑制作用，“-”表示对指定病原体产生小于80％的生长抑制作用，此时掺入生长培养基中的浓度为25ppm。空格表示未作试验。In Table II, "+" indicates that the test material produces at least 80% growth inhibition, and "-" indicates that the specified pathogen produces less than 80% growth inhibition when incorporated into the growth medium at a concentration of 25 ppm. Blanks indicate no experiment.
体内全植物真菌感染控制的生物学评价Biological evaluation of fungal infection control in whole plants in vivo
将工业原料溶于丙酮，然后在丙酮中连续稀释至所需浓度，制成化合物的制剂。因病原体而异，加入9体积的0.05％含水Tween-20或0.01％ Triton X-100，得到最终处理体积。The industrial raw materials are dissolved in acetone, and then serially diluted in acetone to the required concentration to prepare the preparation of the compound. Depending on the pathogen, add 9 volumes of 0.05% aqueous Tween-20 or 0.01% Triton X-100 to give the final treatment volume.
葡萄霜霉(葡萄生单轴霉(Plasmopara viticola)-PLASVI)(24小时保护剂)：种子在无土泥炭类罐装混合物(“Metromix”)中长成藤蔓(cultivar Carignane)，直至幼苗高10-20cm。然后向这些植物按100ppm比例喷以供试化合物。24小时后，向供试植物喷以葡萄生单轴霉的孢子囊水悬液进行接种，保持在露室内过夜。然后将植物转移至温室内，直至在未处理的对照植物上发展为疾病。Downy mildew on grapes (Plasmopara viticola - PLASVI) (24-hour protector): Seeds grown as vines (culvar Carignane) in a soilless peat-based potting mix ("Metromix") until the seedlings were 10 -20cm. The plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the plants to be tested were sprayed with an aqueous suspension of sporangia of Plasmopara viticola to inoculate and kept in the dew room overnight. Plants were then transferred to the greenhouse until disease developed on untreated control plants.
蕃茄晚疫病菌(蔓延疫霉(Phytophthora infestans)-PHYTIN)(24小时保护剂)：种子在无土泥炭类罐装混合物(“Metromix”)中长成蕃茄(cultivar Rutgers)，直至幼苗高10-20cm。然后向这些植物按100ppm比例喷以供试化合物。24小时后，向供试植物喷以蔓延疫霉的孢子囊水悬液进行接种，保持在露室内过夜。然后将植物转移至温室内，直至在未处理的对照植物上发展为疾病。Phytophthora infestans (Phytophthora infestans-PHYTIN) (24-hour protectant): Seeds are grown as cultivar Rutgers in a soilless peat-based potting mix (“Metromix”) until seedlings are 10- 20cm. The plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were sprayed with an aqueous sporangia suspension of Phytophthora infestans for inoculation, and kept in the dew room overnight. Plants were then transferred to the greenhouse until disease developed on untreated control plants.
小麦叶锈病菌(隐匿柄锈菌(Puccinia recondita)-PUCCRT)(24小时保护剂)：种子在无土泥炭类罐装混合物(“Metromix”)中长成小麦(cultivar Yuma)，直至幼苗高10-20cm。然后向这些植物按100ppm比例喷以供试化合物。24小时后，向供试植物喷以隐匿柄锈菌的孢子囊水悬液进行接种，保持在露室内过夜。然后将植物转移至温室内，直至在未处理的对照植物上发展为疾病。Wheat leaf rust (Puccinia recondita - PUCCRT) (24-hour protector): Seeds grown as wheat (culvar Yuma) in a soilless peat-like potting mix ("Metromix") until the seedlings are 10 -20cm. The plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the plants to be tested were sprayed with an aqueous suspension of sporangia of Puccinia reticulata for inoculation, and kept in the dew room overnight. Plants were then transferred to the greenhouse until disease developed on untreated control plants.
小麦白粉病菌(禾白粉菌(Erysiphe graminis)-ERYSGT)(24小时保护剂)：种子在无土泥炭类罐装混合物(“Metromix”)中长成小麦(cultivar Monon)，直至幼苗高10-20cm。然后向这些植物按100ppm比例喷以供试化合物。24小时后，向供试植物撒以粉状霉分生狍子进行接种，感染小麦植物。然后将植物转移至温室内，直至在未处理的对照植物上发展为疾病。Wheat powdery mildew (Erysiphe graminis-ERYSGT) (24-hour protector): Seeds grown as wheat (culvar Monon) in a soilless peat-like pot mix (“Metromix”) until the seedlings are 10-20 cm tall . The plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were inoculated with powdery fungal roe deer to infect the wheat plants. Plants were then transferred to the greenhouse until disease developed on untreated control plants.
小麦叶斑枯病菌(小麦壳针孢(Septoria tritici)-SEPTTR)(24小时保护剂)：种子在无土泥炭类罐装混合物(“Metromix”)中长成小麦(cultivar Yuma)，直至幼苗高10-20cm。然后向这些植物按100ppm比例喷以供试化合物。24小时后，向供试植物喷以小麦壳针孢(Septoria tritici)的孢子水悬液进行接种，保持在露室内过夜。然后将植物转移至温室内，直至在未处理的对照植物上发展为疾病。Leaf spot blight of wheat (Septoria tritici-SEPTTR) (24-hour protectant): Seeds grown as wheat (cultivar Yuma) in a soilless peat-like pot mix (“Metromix”) until seedling height 10-20cm. The plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the plants to be tested were sprayed with an aqueous spore suspension of Septoria tritici for inoculation and kept in the dew room overnight. Plants were then transferred to the greenhouse until disease developed on untreated control plants.
小麦颖斑病菌(Leptosphaeria nodorum-LEPTNO)(24小时保护剂)：种子在无土泥炭类罐装混合物(“Metromix”)中长成小麦(cultivar Yuma)，直至幼苗高10-20cm。然后向这些植物按100ppm比例喷以供试化合物。24小时后，向供试植物喷以Leptosphaerianodorum的孢子水悬液进行接种，保持在露室内过夜。然后将植物转移至温室内，直至在未处理的对照植物上发展为疾病。Leptosphaeria nodorum-LEPTNO (24-hour protector): Seeds were grown as wheat (cultivar Yuma) in a soilless peat-based potting mix ("Metromix") until the seedlings were 10-20 cm tall. The plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were sprayed with an aqueous spore suspension of Leptosphaerianodorum for inoculation, and kept overnight in a dew room. Plants were then transferred to the greenhouse until disease developed on untreated control plants.
表II中，对指定的病原体而言，与未处理的植物发病率相比，“++”表示供试材料产生至少75-100％的真菌感染控制作用，“+”表示供试材料产生25-74％的真菌感染控制作用，“-”表示＜25％的真菌感染控制作用，浓度为100ppm。空格表示未作试验。In Table II, "++" indicates that the test material produces at least 75-100% control of fungal infection, and "+" indicates that the test material produces 25% fungal infection control compared to the incidence of untreated plants for the indicated pathogen. -74% fungal infection control, "-" means <25% fungal infection control, the concentration is 100 ppm. Blanks indicate no experiment.
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优选地本发明化合物以组合物的形式施用，其中包含一种或多种式I化合物与植物学上可接受的载体。组合物是分散在水或另一种施用液体中的浓缩制剂，或者是无需进一步处理即可施用的粉状或颗粒状制剂。组合物是按照农业化学领域中的常规操作加以制备的，但是由于本发明化合物的存在，这些操作是新颖的和重要的。给出组合物制剂的一些说明，以确保农业化学工作者能够容易制备所需的组合物。Preferably the compounds of the invention are applied in the form of compositions comprising one or more compounds of formula I together with a phytologically acceptable carrier. Compositions are concentrated formulations that are dispersed in water or another application liquid, or powdered or granular formulations that are applied without further treatment. The compositions are prepared according to procedures conventional in the field of agrochemistry, but which are novel and significant because of the presence of the compounds of the present invention. Some instructions for the formulation of the compositions are given to ensure that the agrochemist can easily prepare the desired compositions.
采用化合物的分散系最常见为从化合物浓缩制剂制备的水悬液或乳剂。这类水可溶性、水可悬浮性或可乳化性制剂是固体，通常已知为可湿粉剂，或者是液体，通常已知为可乳化性浓缩液或水悬液。本发明涵盖所有能够与本发明化合物配制成杀真菌剂的赋形剂。正如容易认识到的，可以使用任何能够向其中加入这些化合物的材料，只要它们产生所需的实用性而不显著干扰本发明化合物作为杀真菌剂的活性即可。Dispersions employing the compounds are most commonly aqueous suspensions or emulsions prepared from concentrated preparations of the compounds. Such water-soluble, water-suspendable or emulsifiable formulations are solids, commonly known as wettable powders, or liquids, commonly known as emulsifiable concentrates or aqueous suspensions. The invention covers all excipients which can be formulated with the compounds of the invention as fungicides. As will be readily appreciated, any material to which these compounds can be incorporated may be used provided they confer the desired utility without significantly interfering with the activity of the compounds of the present invention as fungicides.
可湿粉剂可以被压缩成水可分散性颗粒，包含活性化合物的紧密混合物、惰性载体和表面活性剂。活性化合物的浓度通常从约10％至约90％w/w，更优选为约25％至约75％w/w。在制备可湿粉剂组合物时，可以将有毒产物与任意微细粉碎的固体混合，例如青磐岩、滑石、白垩、石膏、漂白土、膨润土、石绒、淀粉、酪蛋白、谷蛋白、蒙脱石粘土、硅藻土、纯净硅酸盐等。在这样的操作中，在挥发性有机溶剂中研磨或混合微细粉碎的载体与有毒产物。有效的表面活性剂占可湿粉剂的约0.5％至约10％，包括磺化木质素、萘磺酸盐、烷基苯磺酸盐、烷基硫酸盐，和非离子型表面活性剂，例如烷基酚的氧化乙烯加合物。Wettable powders can be compressed into water-dispersible granules containing an intimate mixture of the active compound, an inert carrier and a surfactant. The concentration of active compound is usually from about 10% to about 90% w/w, more preferably from about 25% to about 75% w/w. In the preparation of wettable powder compositions, the toxic product may be mixed with any finely divided solid such as albado, talc, chalk, gypsum, Fuller's earth, bentonite, stone wool, starch, casein, gluten, montmorillonite Stone clay, diatomaceous earth, pure silicate, etc. In such operations, the finely divided carrier is ground or mixed with the toxic product in a volatile organic solvent. Useful surfactants comprise from about 0.5% to about 10% of the wettable powder and include sulfonated lignins, naphthalene sulfonates, alkylbenzene sulfonates, alkyl sulfates, and nonionic surfactants such as Ethylene oxide adducts of alkylphenols.
本发明化合物的可乳化性浓缩液在适合的液体中包含适宜的浓度，例如从约10％至约50％w/w。化合物是溶解在惰性载体中的，后者是水可混溶性溶剂或者是水不可混溶性有机溶剂与乳化剂的混合物。浓缩液可以用水和油稀释，形成水包油型乳剂形式的喷雾混合物。有用的有机溶剂包括芳族化合物，尤其是石油的高沸点萘属与烯属部分，例如重芳族石脑油。也可以使用其他有机溶剂，例如萜烯溶剂，包括松香衍生物，脂族酮，例如环己酮，和复合醇，例如2-乙氧基乙醇。Emulsifiable concentrates of the compounds of the invention comprise a suitable concentration, for example from about 10% to about 50% w/w, in a suitable liquid. The compound is dissolved in an inert carrier, which is a water-miscible solvent or a mixture of a water-immiscible organic solvent and an emulsifier. The concentrate can be diluted with water and oil to form a spray mixture in the form of an oil-in-water emulsion. Useful organic solvents include aromatics, especially the high boiling naphthalene and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents such as terpene solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol may also be used.
本领域技术人员能够容易地确定这里可以有利采用的乳化剂，包括各种非离子型、阴离子型、阳离子型和两性乳化剂，或者两种或多种乳化剂的掺合物。可用于制备可乳化性浓缩液的非离子型乳化剂实例包括聚亚烷基二醇醚和烷基与芳基酚、脂族醇、脂族胺或脂肪酸与氧化乙烯、氧化丙烯的缩合产物，例如乙氧基化烷基酚，和用多元醇或聚氧化亚烷基增溶的羧酸酯。阳离子型乳化剂包括季铵化合物和脂肪胺盐。阴离子型乳化剂包括烷基芳基磺酸的油可溶性盐(例如钙盐)、硫酸化聚乙二醇醚的油可溶性盐和磷酸化聚乙二醇醚的适当的盐。Those skilled in the art can readily determine emulsifiers which may be advantageously employed herein, including various nonionic, anionic, cationic and amphoteric emulsifiers, or blends of two or more emulsifiers. Examples of nonionic emulsifiers which can be used to prepare emulsifiable concentrates include polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxide, Examples include ethoxylated alkylphenols, and carboxylic acid esters solubilized with polyols or polyoxyalkylenes. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include oil soluble salts of alkylaryl sulfonic acids (eg calcium salts), oil soluble salts of sulfated polyethylene glycol ethers and suitable salts of phosphated polyethylene glycol ethers.
可以用于制备本发明可乳化性浓缩液的代表性有机液体是芳族液体，例如二甲苯、丙基苯馏分或混合的萘馏分、矿物油、取代的芳族有机液体，例如二辛基邻苯二甲酸酯，煤油和各种脂肪酸的二烷基酰胺；特别是脂肪族二甘醇和二甘醇衍生物的二甲基酰胺，例如二甘醇的正丁基醚、乙基醚或甲基醚和三甘醇的甲基醚。在制备可乳化性浓缩液时也经常适合采用两种或多种有机液体的混合物。优选的有机液体是二甲苯和丙基苯馏分，二甲苯是最优选的。在液体组合物中通常采用表面活性分散剂，用量占该分散剂与活性化合物总重量的0.1至20％。活性组合物还可以含有其他可相容的添加剂，例如植物生长调节剂和其他生物学上的活性农用化合物。Representative organic liquids that can be used to prepare the emulsifiable concentrates of the present invention are aromatic liquids such as xylene, propylbenzene fractions or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl o- Dialkylamides of phthalates, kerosene and various fatty acids; especially dimethylamides of aliphatic diethylene glycol and diethylene glycol derivatives, such as n-butyl ether, ethyl ether or methyl ether of diethylene glycol base ethers and methyl ethers of triethylene glycol. Mixtures of two or more organic liquids are also frequently suitable in the preparation of emulsifiable concentrates. Preferred organic liquids are xylene and propylbenzene fractions, with xylene being most preferred. Surface-active dispersants are generally employed in liquid compositions in amounts of from 0.1 to 20% by weight of the combined dispersant and active compound. The active compositions may also contain other compatible additives, such as plant growth regulators and other biologically active agricultural compounds.
水悬液包含本发明的水不溶性化合物分散在水性赋形剂中的悬液，浓度在约5％至约50％w/w的范围内。悬液是这样制备的，将化合物微细研磨，剧烈混合在由水和表面活性剂组成的赋形剂中，表面活性剂选自上文讨论的类型。还可以加入惰性成分，例如无机盐和合成或天然树胶，以增加水性赋形剂的密度和粘度。经常最有效的是在一种工具中制备水性混合物并均化之，例如砂磨机、球磨机或活塞型均化器，同时进行化合物的研磨和混合。Aqueous suspensions comprise a suspension of a water-insoluble compound of the invention dispersed in an aqueous vehicle at a concentration ranging from about 5% to about 50% w/w. Suspensions are prepared by finely grinding the compound and vigorously mixing it in a vehicle consisting of water and a surfactant selected from the types discussed above. Inert ingredients such as inorganic salts and synthetic or natural gums can also be added to increase the density and viscosity of the aqueous vehicle. It is often most efficient to prepare the aqueous mixture and homogenize it in one tool, such as a sand mill, ball mill or piston-type homogenizer, while simultaneously grinding and mixing the compounds.
还可以施用化合物的颗粒状组合物形式，这特别可用于施用于土壤。颗粒状组合物通常含有约0.5％至约10％w/w分散在惰性载体中的化合物，该载体完全或者大部分由粗粉碎的石绒、膨润土、硅藻土、粘土或类似廉价物质组成。这类组合物通常是这样制备的，将化合物溶于适合的溶剂，涂在预成型为适当粒径的颗粒状载体上，粒径在约0.5至约3mm的范围内。这类组合物还可以这样配制，制备载体与化合物的生面团或糊状物，压碎，干燥，得到所需的颗粒。It is also possible to apply the compounds in the form of granular compositions, which are particularly useful for application to the soil. Granular compositions generally contain from about 0.5% to about 10% w/w of the compound dispersed in an inert carrier consisting entirely or largely of coarsely divided stone wool, bentonite, diatomaceous earth, clay or similar inexpensive substances. Such compositions are generally prepared by dissolving the compound in a suitable solvent and coating a particulate carrier preformed to a suitable particle size, ranging from about 0.5 to about 3 mm. Such compositions may also be formulated by preparing a dough or paste of the carrier and compound which is crushed and dried to obtain the desired granules.
含有化合物的粉剂是这样简单制备的，将粉末形式的化合物与适合的粉状农业载体紧密混合，例如高岭土、研磨的火山岩等。粉剂可以适当含有约1％至约10％w/w的化合物。Dusts containing the compound are simply prepared by intimately mixing the compound in powder form with a suitable powdered agricultural carrier, for example kaolin clay, ground volcanic rock and the like. Dusts may suitably contain from about 1% to about 10% w/w compound.
活性组合物可以含有辅助表面活性剂，以增强组合物沉积、湿润和渗透在目标作物和生物上。这些辅助表面活性剂可以可选地用作制剂的组分或罐装混合物。基于水的喷雾体积，辅助表面活性剂的量将从0.01％至1.0％v/v不等，优选为0.05至0.5％。适合的辅助表面活性剂包括乙氧基化壬基苯酚、乙氧基化合成或天然醇、磺基琥珀酸酯的盐、乙氧基化有机硅化合物、乙氧基化脂肪胺和表面活性剂与矿物油或植物油的掺合物。The active composition may contain cosurfactants to enhance deposition, wetting and penetration of the composition onto target crops and organisms. These cosurfactants may optionally be used as components of formulations or pot mixes. The amount of co-surfactant will vary from 0.01% to 1.0% v/v, preferably 0.05 to 0.5%, based on the spray volume of water. Suitable co-surfactants include ethoxylated nonylphenols, ethoxylated synthetic or natural alcohols, salts of sulfosuccinates, ethoxylated silicone compounds, ethoxylated fatty amines and surfactants Blend with mineral or vegetable oil.
组合物可以可选地包括杀真菌剂的组合，其中包含至少1％的一种或多种本发明化合物与另一种杀虫化合物。这类另外的杀虫化合物可以是杀真菌剂、杀昆虫剂、杀线虫剂、杀螨剂、杀节肢动物剂、杀菌剂或它们的组合，它们在为施用而选择的介质中与本发明化合物是可相容的，对本发明化合物的活性不是拮抗性的。因此，在这样的实施方式中，采用其他杀虫化合物作为补充的毒药，用于相同或不同的杀虫用途。化合物在组合物中的比例一般可以从1∶100至100∶1。Compositions may optionally include a fungicide combination comprising at least 1% of one or more compounds of the invention with another pesticidal compound. Such additional pesticidal compounds may be fungicides, insecticides, nematicides, acaricides, arthropodicides, bactericides or combinations thereof, which are mixed with the compounds of the present invention in the medium selected for application. are compatible and are not antagonistic to the activity of the compounds of the invention. Thus, in such embodiments, other pesticidal compounds are employed as complementary poisons for the same or a different pesticidal use. The ratio of the compounds in the composition may generally be from 1:100 to 100:1.
本发明在其范围内包括用于控制或预防真菌侵袭的方法。这些方法包括向真菌部位或所要预防感染的部位(例如施用于谷类或葡萄植物)施用杀真菌量的一种或多种本发明化合物或组合物。化合物在杀真菌水平下适合于治疗各种植物，且植物毒性低。化合物可以采用保护剂或根除剂的方式。按照任意各种已知工艺施用本发明化合物，既可以是化合物也可以是包括化合物的组合物。例如，化合物可以被施用于植物的根、种子或叶，用于控制各种真菌，而不损害植物的商业价值。施用采取任意常用的制剂类型，例如溶液、粉剂、可湿粉剂、可流动性浓缩液或可乳化性浓缩液。这些制剂适宜以各种已知的模式施用。The present invention includes within its scope methods for controlling or preventing fungal infestation. These methods comprise applying a fungicidal amount of one or more compounds or compositions of the invention to the fungal locus or locus where infection is to be prevented (eg to cereal or grape plants). The compounds are suitable for treating a variety of plants at fungicidal levels with low phytotoxicity. The compounds can take the form of protectants or eradicators. Administration of the compounds of the present invention, either as compounds or compositions comprising compounds, follows any of a variety of known techniques. For example, compounds can be applied to the roots, seeds or leaves of plants for the control of various fungi without compromising the commercial value of the plants. Administration takes any of the usual formulation types, such as solutions, powders, wettable powders, flowable concentrates or emulsifiable concentrates. These formulations are suitably administered in various known modes.
已经发现本发明化合物具有显著的杀真菌效果，特别可用于农业用途。很多化合物特别有效地用于农业作物和园艺植物或木材、涂料、皮革或地毯衬垫。The compounds according to the invention have been found to have a pronounced fungicidal effect and are particularly useful for agricultural use. Many compounds are particularly effective for use on agricultural crops and horticultural plants or on wood, paint, leather or carpet underlays.
确切地说，化合物有效控制各种不希望有的真菌，它们感染有用的植物作物。已经证明了对各种真菌的活性，例如包括下列代表性真菌物种：葡萄霜霉(葡萄生单轴霉(Plasmopara viticola)-PLASVI)、蕃茄晚疫病菌(蔓延疫霉(Phytophthora infestans)-PHYTIN)、苹果斑点病菌(苹果黑星菌(Venturia inaequalis)-VENTIN)、小麦叶锈病菌(隐匿柄锈菌(Puccinia recondita)-PUCCRT)、小麦秆锈病菌(条形柄锈菌(Puccinia striiformis)-PUCCST)、稻瘟病菌(Pyricularia oryzae-PYRIOR)、甜菜尾孢菌叶斑病菌(甜菜尾孢(Cercospora beticola)-CERCBE)、小麦白粉病菌(禾白粉菌(Erysiphe graminis)-ERYSGT)、小麦叶斑枯病菌(小麦壳针孢(Septoria tritici)-SEPTTR)、稻叶鞘枯萎病菌(茄属丝核菌(Rhizoctonia solani)-RHIZSO)、小麦眼斑病菌(Pseudocercosporella herpotrichoides-PSDCHE)、桃树褐枯病菌(果生链核盘菌(Monilinia fructicola)-MONIFC)和小麦颖斑病菌(Leptosphaeria nodorum-LEPTNO)。对本领域来说将不言而喻的是本发明化合物对上述真菌的功效确立了该化合物作为杀真菌剂的普遍实用性。Specifically, the compounds are effective in controlling various undesirable fungi which infect crops of useful plants. Activity has been demonstrated against a variety of fungi including, for example, the following representative fungal species: Peronospora vine (Plasmopara viticola - PLASVI), Infestans tomato (Phytophthora infestans - PHYTIN) , Apple spot fungus (Venturia inaequalis-VENTIN), wheat leaf rust fungus (Puccinia recondita-PUCCRT), wheat stem rust fungus (Puccinia striiformis-PUCCST ), Pyricularia oryzae-PYRIOR, Cercospora beticola-CERCBE, Wheat powdery mildew (Erysiphe graminis-ERYSGT), Wheat leaf spot Pathogen (Septoria tritici-SEPTTR), rice leaf sheath wilt (Rhizoctonia solani-RHIZSO), wheat eye spot (Pseudocercosporella herpotrichoides-PSDCHE), peach brown blight (fruit Streptococcus sclerotiorum (Monilinia fructicola)-MONIFC) and wheat leaf spot fungus (Leptosphaeria nodorum-LEPTNO). It will be self-evident to the art that the efficacy of the compounds of the invention against the fungi described above establishes the general utility of the compounds as fungicides.
本发明化合物作为杀真菌剂具有广谱功效。活性物质的精确用量不仅取决于所用具体活性物质，而且取决于所需的特定作用、所要控制的真菌物种及其生长阶段以及与毒性活性成分接触的植物或其他产品的部位。因而，所有本发明化合物和含有该化合物的组合物的活性成分在近似浓度下或者对相同真菌物种可能不是同等有效的。本发明化合物和组合物在抑制疾病和植物学上可接受的用量下对植物是有效的。The compounds of the present invention have broad-spectrum efficacy as fungicides. The precise amount of active substance to be used depends not only on the specific active substance used, but also on the specific action desired, the fungal species and its growth stage to be controlled, and the part of the plant or other product that comes into contact with the toxic active ingredient. Thus, all compounds of the invention and active ingredients of compositions containing such compounds may not be equally effective at similar concentrations or against the same fungal species. The compounds and compositions of the present invention are effective on plants at disease inhibiting and phytologically acceptable amounts.
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| US60/150,248 | 1999-08-23 | ||
| US09/620,662 US6521622B1 (en) | 1999-07-20 | 2000-07-20 | Fungicidal heterocyclic aromatic amides and their compositions, methods of use and preparation |
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- 2000-08-04 CN CN00811652.0A patent/CN1237051C/en not_active Expired - Fee Related
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- 2000-08-04 BR BRPI0013469-4A patent/BR0013469B1/en not_active IP Right Cessation
- 2000-08-04 EP EP00952599A patent/EP1204643B1/en not_active Expired - Lifetime
- 2000-08-04 AT AT00952599T patent/ATE397590T1/en active
- 2000-08-04 CA CA002376275A patent/CA2376275A1/en not_active Abandoned
- 2000-08-04 ES ES00952599T patent/ES2307525T3/en not_active Expired - Lifetime
- 2000-08-04 WO PCT/US2000/021523 patent/WO2001014339A2/en not_active Ceased
- 2000-08-04 JP JP2001518428A patent/JP2003527324A/en active Pending
- 2000-08-04 TR TR2002/00409T patent/TR200200409T2/en unknown
- 2000-08-04 PL PL360097A patent/PL205059B1/en unknown
- 2000-08-04 CZ CZ2002487A patent/CZ2002487A3/en unknown
- 2000-08-04 HU HU0300924A patent/HU228503B1/en not_active IP Right Cessation
- 2000-08-04 AU AU65267/00A patent/AU778108B2/en not_active Ceased
- 2000-08-04 DE DE60039115T patent/DE60039115D1/en not_active Expired - Lifetime
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| CN100402525C (en) * | 2003-02-19 | 2008-07-16 | 拜尔农科股份有限公司 | Pyridine derivatives as fungicidal compounds |
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| CN103328484A (en) * | 2010-09-03 | 2013-09-25 | 拜耳知识产权有限责任公司 | Dithiine tetra(thio)carboximide |
| CN103339104A (en) * | 2010-11-15 | 2013-10-02 | 拜耳知识产权有限责任公司 | Decahydro-1,4-methylenenaphthalenecarboxamide |
| CN104470910A (en) * | 2012-05-07 | 2015-03-25 | 陶氏益农公司 | Macrocyclic-2-picolin amides as fungicides |
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| CN105745205A (en) * | 2013-10-01 | 2016-07-06 | 美国陶氏益农公司 | Use of macrocyclic picolinamides as fungicides |
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| CN107205405B (en) * | 2014-12-30 | 2021-08-24 | 美国陶氏益农公司 | Pyridinamide compounds with fungicidal activity |
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| CN108349915A (en) * | 2015-11-04 | 2018-07-31 | 先正达参股股份有限公司 | Microbicidal aniline derivatives |
| CN109068653A (en) * | 2016-02-29 | 2018-12-21 | 美国陶氏益农公司 | The method for preparing 4- alkoxy -3- hydroxy-picolinic acid |
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Also Published As
| Publication number | Publication date |
|---|---|
| CN1237051C (en) | 2006-01-18 |
| PL205059B1 (en) | 2010-03-31 |
| PT1204643E (en) | 2008-09-15 |
| EP1204643B1 (en) | 2008-06-04 |
| CZ2002487A3 (en) | 2002-06-12 |
| AU778108B2 (en) | 2004-11-18 |
| EP1204643A2 (en) | 2002-05-15 |
| HUP0300924A2 (en) | 2003-08-28 |
| WO2001014339A2 (en) | 2001-03-01 |
| HU228503B1 (en) | 2013-03-28 |
| ATE397590T1 (en) | 2008-06-15 |
| CA2376275A1 (en) | 2001-03-01 |
| ES2307525T3 (en) | 2008-12-01 |
| BR0013469A (en) | 2003-04-29 |
| DE60039115D1 (en) | 2008-07-17 |
| HUP0300924A3 (en) | 2003-10-28 |
| TR200200409T2 (en) | 2003-03-21 |
| BR0013469B1 (en) | 2011-01-25 |
| PL360097A1 (en) | 2004-09-06 |
| WO2001014339A3 (en) | 2001-11-15 |
| JP2003527324A (en) | 2003-09-16 |
| AU6526700A (en) | 2001-03-19 |
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